U.S. patent application number 17/631972 was filed with the patent office on 2022-09-08 for compounds, pharmaceutical compositions, and methods of their use in the inhibition of interaction between il18 and il18r.
The applicant listed for this patent is Beth Israel Deaconess Medical Center, Inc.. Invention is credited to Gabriel BIRANNE, Finith JERNIGAN, Frank W. LOGERFO, Philip LOGERFO, Leena PRADHAN-NABZDYK, Lijun SUN.
Application Number | 20220281802 17/631972 |
Document ID | / |
Family ID | 1000006380968 |
Filed Date | 2022-09-08 |
United States Patent
Application |
20220281802 |
Kind Code |
A1 |
PRADHAN-NABZDYK; Leena ; et
al. |
September 8, 2022 |
COMPOUNDS, PHARMACEUTICAL COMPOSITIONS, AND METHODS OF THEIR USE IN
THE INHIBITION OF INTERACTION BETWEEN IL18 AND IL18R
Abstract
Compounds, pharmaceutical compositions, and methods are
disclosed for inhibiting interaction between IL18 and IL18R.
Inventors: |
PRADHAN-NABZDYK; Leena;
(Rochester, MN) ; SUN; Lijun; (Harvard, MA)
; LOGERFO; Philip; (Cambridge, MA) ; JERNIGAN;
Finith; (Brookline, MA) ; BIRANNE; Gabriel;
(Lynn, MA) ; LOGERFO; Frank W.; (Cambridge,
MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Beth Israel Deaconess Medical Center, Inc. |
Boston |
MA |
US |
|
|
Family ID: |
1000006380968 |
Appl. No.: |
17/631972 |
Filed: |
July 31, 2020 |
PCT Filed: |
July 31, 2020 |
PCT NO: |
PCT/US2020/044636 |
371 Date: |
February 1, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62881679 |
Aug 1, 2019 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07C 279/18 20130101;
C07D 249/18 20130101; C07C 2601/16 20170501; C07D 401/04 20130101;
C07C 211/45 20130101 |
International
Class: |
C07C 211/45 20060101
C07C211/45; C07D 249/18 20060101 C07D249/18; C07C 279/18 20060101
C07C279/18; C07D 401/04 20060101 C07D401/04 |
Goverment Interests
STATEMENT AS TO FEDERALLY FUNDED RESEARCH
[0001] The invention was made with Government support under Grant
No. HL133821 awarded by the National Institutes of Health. The
government has certain rights in the invention.
Claims
1. A compound of formula (I): ##STR00089## or a pharmaceutically
acceptable salt thereof, wherein: each of X.sup.1, X.sup.2,
X.sup.3, X.sup.4, X.sup.5, X.sup.6, X.sup.7, X.sup.8, X.sup.9, and
X.sup.10 is independently CR.sup.1 or N; Y is O, C(R.sup.2).sub.2,
or S(O).sub.t; each R.sup.1 is independently hydrogen, halogen,
hydroxyl, cyano, nitro, --N(R.sup.3).sub.2, --S(O).sub.tR.sup.4,
--OR.sup.3, optionally substituted C.sub.1-C.sub.6 alkyl,
optionally substituted C.sub.6-C.sub.10 aryl, optionally
substituted C.sub.3-C.sub.8 cycloalkyl, optionally substituted
heteroaryl, or optionally substituted heterocyclyl; each R.sup.2 is
independently hydrogen or optionally substituted C.sub.1-C.sub.6
alkyl; or both R.sup.2 combine to form .dbd.O, .dbd.S, or
.dbd.NR.sup.5; R.sup.3 is hydrogen, --SO.sub.2R.sup.4, optionally
substituted C.sub.1-C.sub.6 alkyl, optionally substituted
C.sub.6-C.sub.10 aryl, optionally substituted C.sub.3-C.sub.8
cycloalkyl, optionally substituted heteroaryl, or optionally
substituted heterocyclyl; each R.sup.4 is independently optionally
substituted C.sub.1-C.sub.6 alkyl, optionally substituted
C.sub.6-C.sub.10 aryl, optionally substituted heteroaryl, or
optionally substituted heterocyclyl; R.sup.5 is hydrogen, hydroxyl,
--S(O).sub.2R.sup.4, or optionally substituted C.sub.1-C.sub.6
alkyl; each t is independently 0, 1, or 2; and the compound of
formula (I) is not a compound selected from the group consisting
of: ##STR00090## and pharmaceutically acceptable salts thereof; and
provided that at least one of X.sup.1, X.sup.2, X.sup.3, X.sup.4,
and X.sup.5 is CR.sup.1, at least one of X.sup.6, X.sup.7, X.sup.8,
X.sup.9, and X.sup.10 is CR.sup.1, and at least one R.sup.1 is
halogen, hydroxyl, cyano, nitro, --N(R.sup.3).sub.2,
--S(O).sub.tR.sup.4, --OR.sup.3, or optionally substituted
C.sub.1-C.sub.6 alkyl.
2. The compound of claim 1, wherein Y is C(R.sup.2).sub.2.
3. The compound of claim 1, wherein at least one R.sup.2 is
hydrogen.
4. The compound of claim 1, wherein both R.sup.2 combine to form
.dbd.O.
5. The compound of claim 1, wherein each R.sup.2 is independently
optionally substituted C.sub.1-C.sub.6 alkyl.
6. The compound of claim 1, wherein each of X.sup.2 and X.sup.9 is
independently CR.sup.1.
7. The compound of claim 1, wherein at least two R.sup.1 groups are
--N(R.sup.3).sub.2.
8. The compound of claim 1, wherein the compound is a compound of
formula (Ia): ##STR00091## or a pharmaceutically acceptable salt
thereof, wherein: each R.sup.1 is independently halogen, hydroxyl,
cyano, nitro, --N(R.sup.3).sub.2, --S(O)R.sup.4, --OR.sup.3,
optionally substituted C.sub.1-C.sub.6 alkyl, optionally
substituted C.sub.6-C.sub.10aryl, optionally substituted
C.sub.3-C.sub.8cycloalkyl, or optionally substituted
heteroaryl.
9. The compound of claim 1, wherein the compound is a compound of
formula (Ib): ##STR00092## or a pharmaceutically acceptable salt
thereof.
10. The compound of claim 8, wherein R.sup.2 is hydrogen, hydroxyl,
or optionally substituted C.sub.1-C.sub.6 alkyl.
11. A pharmaceutical composition comprising a compound of formula
(I): ##STR00093## or a pharmaceutically acceptable salt thereof,
wherein: each of X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5,
X.sup.6, X.sup.7, X.sup.8, X.sup.9, and X.sup.10 is independently
CR.sup.1 or N; Y is O, C(R.sup.2).sub.2, or S(O).sub.t; each
R.sup.1 is independently hydrogen, halogen, hydroxyl, cyano, nitro,
--N(R.sup.3).sub.2, --S(O).sub.tR.sup.4, --OR.sup.3, optionally
substituted C.sub.1-C.sub.6 alkyl, optionally substituted
C.sub.6-C.sub.10 aryl, optionally substituted C.sub.3-C.sub.8
cycloalkyl, optionally substituted heteroaryl, or optionally
substituted heterocyclyl; each R.sup.2 is independently hydrogen,
hydroxyl, or optionally substituted C.sub.1-C.sub.6alkyl; or both
R.sup.2 combine to form .dbd.O, .dbd.S, or .dbd.NR.sup.5; R.sup.3
is hydrogen, --SO.sub.2R.sup.4, optionally substituted
C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.6-C.sub.10
aryl, optionally substituted C.sub.3-C.sub.8 cycloalkyl, optionally
substituted heteroaryl, or optionally substituted heterocyclyl;
each R.sup.4 is independently optionally substituted
C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.6-C.sub.10
aryl, optionally substituted heteroaryl, or optionally substituted
heterocyclyl; R.sup.5 is hydrogen, hydroxyl, --S(O).sub.2R.sup.4,
or optionally substituted C.sub.1-C.sub.6 alkyl; and each t is
independently 0, 1, or 2.
12. The pharmaceutical composition of claim 11, wherein Y is
C(R.sup.2).sub.2.
13. The pharmaceutical composition of claim 11, wherein at least
one R.sup.2 is hydrogen.
14. The pharmaceutical composition of claim 11, wherein both
R.sup.2 combine to form .dbd.O.
15. The pharmaceutical composition of claim 11, wherein each
R.sup.2 is independently optionally substituted C.sub.1-C.sub.6
alkyl.
16. The pharmaceutical composition of claim 11, wherein each of
X.sup.2 and X.sup.9 is independently CR.sup.1.
17. The pharmaceutical composition of claim 11, wherein at least
two R.sup.1 groups are --N(R.sup.3).sub.2.
18. The pharmaceutical composition of claim 11, wherein the
compound is a compound of formula (Ia): ##STR00094## or a
pharmaceutically acceptable salt thereof, wherein: each R.sup.1 is
independently halogen, hydroxyl, cyano, nitro, --N(R.sup.3).sub.2,
--S(O).sub.tR.sup.4, --OR.sup.3, optionally substituted
C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.6-C.sub.10aryl,
optionally substituted C.sub.3-C.sub.8cycloalkyl, or optionally
substituted heteroaryl.
19. The pharmaceutical composition of claim 11, wherein the
compound is a compound of formula (Ib): ##STR00095## or a
pharmaceutically acceptable salt thereof.
20. The pharmaceutical composition of claim 19, wherein R.sup.2 is
hydrogen, hydroxyl, or optionally substituted C.sub.1-C.sub.6
alkyl.
21. A pharmaceutical composition comprising a compound selected
from the group consisting of: ##STR00096## and pharmaceutically
acceptable salts thereof.
22. A compound of formula (II): ##STR00097## or a pharmaceutically
acceptable salt thereof, wherein: (i) R.sup.1A and R.sup.1B combine
to form .dbd.O, .dbd.S, .dbd.C(R.sup.6).sub.2, or .dbd.NR.sup.7;
R.sup.2A and R.sup.2B combine to form .dbd.O, .dbd.S,
.dbd.C(R.sup.6).sub.2, or .dbd.NR.sup.7; and R.sup.3A and R.sup.3B,
together with the atoms to which they are attached, combine to form
a double bond; or (ii) each of R.sup.1A and R.sup.2A is
independently hydrogen, halogen, hydroxyl, cyano, nitro,
--S(O)R.sup.6, or --OR.sup.7; R.sup.1B and R.sup.3A, together with
the atoms to which they are attached, combine to form a double
bond; and R.sup.2B and R.sup.3B, together with the atoms to which
they are attached, combine to form a double bond; both R.sup.4,
together with the atoms to which they are attached, combine to form
an optionally substituted heterocyclic ring; both R.sup.5, together
with the atoms to which they are attached, combine to form an
optionally substituted heterocyclic ring; each R.sup.6 is
independently hydrogen, halogen, cyano, or optionally substituted
C.sub.1-C.sub.6 alkyl; each R.sup.7 is independently hydroxyl,
optionally substituted C.sub.1-C.sub.6 alkyl, optionally
substituted C.sub.6-C.sub.10 aryl, optionally substituted
C.sub.3-C.sub.8 cycloalkyl, optionally substituted heteroaryl, or
optionally substituted heterocyclyl; each t is independently 0, 1,
or 2; and the compound of formula (II) is not a compound selected
from the group consisting of: ##STR00098## and pharmaceutically
acceptable salts thereof.
23. The compound of claim 22, wherein both R.sup.4, together with
the atoms to which they are attached, combine to form an optionally
substituted heterocyclic ring comprising an endocyclic nitrogen
atom.
24. The compound of claim 22, wherein both R.sup.4, together with
the atoms to which they are attached, combine to form an optionally
substituted, 5-membered heterocyclic ring.
25. The compound of claim 22, wherein both R.sup.5, together with
the atoms to which they are attached, combine to form an optionally
substituted heterocyclic ring comprising an endocyclic nitrogen
atom.
26. The compound of claim 22, wherein both R.sup.5, together with
the atoms to which they are attached, combine to form an optionally
substituted, 5-membered heterocyclic ring.
27. The compound of claim 22, wherein the compound is a compound of
formula (IIa): ##STR00099## or a pharmaceutically acceptable salt
thereof, and each R.sup.8 is independently H or optionally
substituted C.sub.1-C.sub.6 alkyl.
28. The compound of claim 22, wherein R.sup.1A and R.sup.1B combine
to form .dbd.O.
29. The compound of claim 22, wherein R.sup.2A and R.sup.2B combine
to form .dbd.O.
30. The compound of claim 22, wherein each of R.sup.1A and R.sup.2A
is independently hydrogen, halogen, or hydroxyl.
31. A pharmaceutical composition comprising a compound of formula
(II): ##STR00100## or a pharmaceutically acceptable salt thereof,
wherein: (i) R.sup.1A and R.sup.1B combine to form .dbd.O, .dbd.S,
.dbd.C(R.sup.6).sub.2, or .dbd.NR.sup.7; R.sup.2A and R.sup.2B
combine to form .dbd.O, .dbd.S, .dbd.C(R.sup.6).sub.2, or
.dbd.NR.sup.7; and R.sup.3A and R.sup.3B, together with the atoms
to which they are attached, combine to form a double bond; or (ii)
each of R.sup.1A and R.sup.2A is independently hydrogen, halogen,
hydroxyl, cyano, nitro, --S(O)R.sup.6, or --OR.sup.7; R.sup.1B and
R.sup.3A, together with the atoms to which they are attached,
combine to form a double bond; and R.sup.2B and R.sup.3B, together
with the atoms to which they are attached, combine to form a double
bond; both R.sup.4, together with the atoms to which they are
attached, combine to form an optionally substituted heterocyclic
ring; both R.sup.5, together with the atoms to which they are
attached, combine to form an optionally substituted heterocyclic
ring; each R.sup.6 is independently hydrogen, halogen, cyano, or
optionally substituted C.sub.1-C.sub.6 alkyl; each R.sup.7 is
independently hydroxyl, optionally substituted C.sub.1-C.sub.6
alkyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally
substituted C.sub.3-C.sub.8 cycloalkyl, optionally substituted
heteroaryl, or optionally substituted heterocyclyl; and each t is
independently 0, 1, or 2.
32. The pharmaceutical composition of claim 31, wherein both
R.sup.4, together with the atoms to which they are attached,
combine to form an optionally substituted heterocyclic ring
comprising an endocyclic nitrogen atom.
33. The pharmaceutical composition of claim 31, wherein both
R.sup.4, together with the atoms to which they are attached,
combine to form an optionally substituted, 5-membered heterocyclic
ring.
34. The pharmaceutical composition of claim 31, wherein both
R.sup.5, together with the atoms to which they are attached,
combine to form an optionally substituted heterocyclic ring
comprising an endocyclic nitrogen atom.
35. The pharmaceutical composition of claim 31, wherein both
R.sup.5, together with the atoms to which they are attached,
combine to form an optionally substituted, 5-membered heterocyclic
ring.
36. The pharmaceutical composition of claim 31, wherein the
compound is a compound of formula (IIa): ##STR00101## or a
pharmaceutically acceptable salt thereof, and each R.sup.8 is
independently H or optionally substituted C.sub.1-C.sub.6
alkyl.
37. The pharmaceutical composition of claim 31, wherein R.sup.1A
and R.sup.1B combine to form .dbd.O.
38. The pharmaceutical composition of claim 31, wherein R.sup.2A
and R.sup.2B combine to form .dbd.O.
39. The pharmaceutical composition of claim 31, wherein each of
R.sup.1A and R.sup.2A is independently hydrogen, halogen, or
hydroxyl.
40. A pharmaceutical composition comprising a compound selected
from the group consisting of: ##STR00102## and pharmaceutically
acceptable salts thereof.
41. A compound of formula (III): ##STR00103## or a pharmaceutically
acceptable salt thereof, wherein: R.sup.1 is an optionally
substituted C.sub.6-C.sub.10 aryl or optionally substituted
heteroaryl; each R.sup.2 is independently hydrogen or an optionally
substituted C.sub.1-C.sub.6 alkyl; and the compound of formula
(III) is not a compound selected from the group consisting of:
##STR00104## and pharmaceutically acceptable salts thereof.
42. The compound of claim 41, wherein R.sup.1 is optionally
substituted C.sub.6-C.sub.10 aryl.
43. The compound of claim 41, wherein each R.sup.2 is hydrogen.
44. The compound of claim 41, wherein the compound is a compound of
formula (IIIa): ##STR00105## or a pharmaceutically acceptable salt
thereof, wherein: R.sup.3 is optionally substituted C.sub.1-C.sub.6
alkyl, halogen, --OR.sup.4, --S(O)R.sup.5, or --N(R.sup.4).sub.2;
each R.sup.4 is independently hydrogen or optionally substituted
C.sub.1-C.sub.6 alkyl; R.sup.5 is optionally substituted
C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.6-C.sub.10
aryl, or optionally substituted heteroaryl.
45. The compound of claim 44, wherein R.sup.3 is optionally
substituted C.sub.1-C.sub.6 alkyl or halogen.
46. A pharmaceutical composition comprising a compound of formula
(III): ##STR00106## or a pharmaceutically acceptable salt thereof,
wherein: R.sup.1 is an optionally substituted C.sub.6-C.sub.10 aryl
or optionally substituted heteroaryl; and each R.sup.2 is
independently hydrogen or an optionally substituted C.sub.1-C.sub.6
alkyl.
47. The pharmaceutical composition of claim 46, wherein R.sup.1 is
optionally substituted C.sub.6-C.sub.10 aryl.
48. The pharmaceutical composition of claim 46, wherein each
R.sup.2 is hydrogen.
49. The pharmaceutical composition of claim 46, wherein the
compound is a compound of formula (IIIa): ##STR00107## or a
pharmaceutically acceptable salt thereof, wherein: R.sup.3 is
hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, halogen,
cyano, --OR.sup.4, --S(O)R.sup.5, or --N(R.sup.4).sub.2; each
R.sup.4 is independently hydrogen or optionally substituted
C.sub.1-C.sub.6 alkyl; R.sup.5 is optionally substituted
C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.6-C.sub.10
aryl, or optionally substituted heteroaryl; and each t is
independently 0, 1, or 2.
50. The pharmaceutical composition of claim 49, wherein R.sup.3 is
optionally substituted C.sub.1-C.sub.6 alkyl, hydrogen, halogen, or
cyano.
51. A pharmaceutical composition comprising a compound selected
from the group consisting of: ##STR00108## and pharmaceutically
acceptable salts thereof.
52. A method of inhibiting interaction between IL18 and IL18R in a
medium comprising IL18 and a cell expressing IL18R, the method
comprising contacting the cell in the medium with a compound of any
one of claims 1 to 51, wherein after the contacting step the
interaction between IL18 and IL18R is inhibited.
53. The method of claim 52, wherein the cell is in a subject.
54. The method of claim 52, wherein the medium is a tissue or
bodily fluid of a subject.
55. A method of treating an inflammatory or autoimmune disorder in
a subject in need thereof, the method comprising administering a
therapeutically effective amount of the compound of claim 1, or a
pharmaceutically acceptable salt thereof, to the subject.
56. The method of claim 55, wherein the inflammatory or autoimmune
disorder is selected from the group consisting of rheumatoid
arthritis, osteoarthritis, lupus, psoriasis, inflammatory bowel
disease, vascular graft failure, heart disease, vascular disease,
type 1 diabetes, type 2 diabetes, metabolic syndrome, diabetic
wound healing, trauma, burn wounds, Steven Johnsons syndrome, and
kidney disease.
57. The method of claim 56, wherein the inflammatory or autoimmune
disorder is a vascular graft failure.
58. The method of claim 57, wherein the vascular graft failure is a
peripheral vascular graft failure.
59. The method of claim 58, wherein the peripheral vascular graft
failure is a vein graft failure or prosthetic graft failure.
60. The method of claim 57, wherein the vascular graft failure is a
coronary artery graft failure.
61. The method of claim 60, wherein the coronary graft failure is
an is artery graft failure, vein graft failure, prosthetic graft
failure.
62. The method of claim 57, wherein the vascular graft failure is
restenosis after stent graft.
63. The method of claim 57, wherein the vascular graft failure is
restenosis after balloon angioplasty.
64. The method of claim 56, wherein the inflammatory or autoimmune
disorder is a heart disease.
65. The method of claim 64, wherein the heart disease is
cardiomyopathy, congestive heart failure, or ischemic coronary
heart disease.
66. The method of claim 55, wherein the inflammatory or autoimmune
disorder is a vascular disease.
67. The method of claim 66, wherein the vascular disease is intimal
hyperplasia, atherosclerosis, coronary artery disease, restenosis,
primary hypertension, secondary hypertension, peripheral vascular
disease, or critical limb-threatening ischemia.
68. The method of claim 56, wherein the inflammatory or autoimmune
disorder is type 1 diabetes, type 2 diabetes, metabolic syndrome,
or diabetic wound healing.
69. The method of claim 56, wherein the inflammatory or autoimmune
disorder is a kidney disease.
70. The method of claim 69, wherein the kidney disease is a chronic
kidney disease, end-stage renal disease, or kidney failure.
71. The method of claim 55, wherein the inflammatory or autoimmune
disorder is a cytokine storm.
72. The method of claim 55, wherein the inflammatory or autoimmune
disorder is endothelialitis.
73. The method of claim 55, wherein the subject is suffering from
acute respiratory distress syndrome (ARDS).
74. The method of claim 55, wherein the inflammatory or autoimmune
disorder is associated with an infection.
75. The method of claim 74, wherein the infection is a
beta-coronavirus infection.
76. The method of claim 75, wherein the infection is SARS-CoV-2,
SARS-CoV, or MERS-CoV.
77. The method of claim 76, wherein the infection is
SARS-CoV-2.
78. The method of claim 55, wherein the inflammatory or autoimmune
disorder is sepsis.
79. The method of claim 55, wherein the inflammatory or autoimmune
disorder is associated with a viremia, bacteremia, protozoan
infection, or fungal infection.
80. A method of treating a cancer in a subject in need thereof, the
method comprising administering a therapeutically effective amount
of the compound of claim 1, or a pharmaceutically acceptable salt
thereof, to the subject.
81. The method of claim 80, wherein the cancer is gastric cancer,
colon cancer, melanoma, and multiple myeloma.
Description
FIELD OF THE INVENTION
[0002] The invention relates to compounds, pharmaceutical
compositions, and methods of their use in the inhibition of
interaction between interleukin-18 (IL18) and the interleukin-18
receptor (IL18R).
BACKGROUND
[0003] Interleukin-18 (IL18) is a pleiotropic pro-inflammatory
cytokine belonging to the IL-1 superfamily. IL18 plays an important
role in host innate and adaptive immune defense against pathogenic
infections. Despite the significant role of IL18 in host immune
responses against infection, aberrant hIL18 bioactivity also has
been associated with inflammatory and autoimmune disorders,
allergies, and neurological disorders. In fact, it has been shown
that increased levels of mature hIL18 have a direct correlation
with the severity of pathological autoimmune disorders such as
Multiple Sclerosis (MS), Rheumatoid Arthritis (RA), and lupus. A
current strategy for treating these human diseases is to target
proteins involved in the initiation event(s) of inflammation or
upstream events of the innate immune response. These upstream
effector proteins include but are not limited to Cyclooxygenase-2
(Cox-2) and caspase-1, which respond to Non-Steroidal
Anti-Inflammatory Drugs (NSAID) and specific caspase inhibitors,
respectively. However, these treatments suffer from side effects,
such as colitis.
[0004] IL18 was originally referred to as IFN-.gamma. Inducing
Factor (IGIF) for its ability to stimulate the production of
IFN-.gamma.. IL18 stimulates IFN-.gamma. production from T-helper
lymphocytes (Th1) and macrophages, and enhances the cytotoxicity of
natural killer (NK) cells. The IL18 stimulated IFN-.gamma.
production is synergistically amplified with other Th1-related
cytokines, IL-2, IL-15, IL-12, and IL-23. IL18 is synthesized as a
23 kDa inactive precursor, which is subsequently cleaved into an 18
kDa active form by a member of the inflammasome
(Interleukin-1.beta. Converting Enzyme, ICE (Caspase-1) and then
secreted, resulting in the initiation of IL18 signaling cascade.
IL18 signals through its two membrane bound receptors, IL18R.alpha.
and IL18R.beta., forming a ternary complex necessary for productive
intracellular signaling.
[0005] IL18 activity is modulated in vivo by its naturally
occurring antagonist, Interleukin-18 Binding Protein (IL18BP), a
soluble protein including a single immunoglobulin (Ig) domain. The
human IL18BP (hIL18BP) has an exceptionally high affinity for hIL18
of 400 pM and has been shown to be up-regulated in various cell
lines in response to elevated IFN-.gamma. levels, suggesting that
it serves as a negative feedback inhibitor of hIL18 mediated immune
responses. hIL18BP has also been shown to be effective at treating
inflammatory skin diseases and lipopolysaccharide (LPS)-induced
liver injury, but has also met with complications often causing
immunogenic reaction themselves.
[0006] There is a need for IL18 inhibitors for, e.g., the treatment
of inflammatory or autoimmune disorders and cancer.
SUMMARY OF THE INVENTION
[0007] In one aspect, the invention features a compound according
to formula (I):
##STR00001##
or a pharmaceutically acceptable salt thereof,
Where:
[0008] each of X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5,
X.sup.6, X.sup.7, X.sup.8, X.sup.9, and X.sup.10 is independently
CR.sup.1 or N;
[0009] Y is O, C(R.sup.2).sub.2, or S(O).sub.t;
[0010] each R.sup.1 is independently hydrogen, halogen, hydroxyl,
cyano, nitro, --N(R.sup.3).sub.2, --S(O).sub.tR.sup.4, --OR.sup.3,
optionally substituted C.sub.1-C.sub.6 alkyl, optionally
substituted C.sub.6-C.sub.10 aryl, optionally substituted
C.sub.3-C.sub.8 cycloalkyl, optionally substituted heteroaryl, or
optionally substituted heterocyclyl;
[0011] each R.sup.2 is independently hydrogen or optionally
substituted C.sub.1-C.sub.6 alkyl; or both R.sup.2 combine to form
.dbd.O, .dbd.S, or .dbd.NR.sup.5;
[0012] R.sup.3 is hydrogen, --SO.sub.2R.sup.4, optionally
substituted C.sub.1-C.sub.6 alkyl, optionally substituted
C.sub.6-C.sub.10 aryl, optionally substituted C.sub.3-C.sub.8
cycloalkyl, optionally substituted heteroaryl, or optionally
substituted heterocyclyl;
[0013] each R.sup.4 is independently optionally substituted
C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.6-C.sub.10
aryl, optionally substituted heteroaryl, or optionally substituted
heterocyclyl;
[0014] R.sup.5 is hydrogen, hydroxyl, --S(O).sub.2R.sup.4,
optionally substituted C.sub.1-C.sub.6 alkyl;
[0015] each t is independently 0, 1, or 2; and
[0016] In particular embodiments, the compound of formula (I) is
not a compound selected from the group consisting of:
##STR00002##
and pharmaceutically acceptable salts thereof.
[0017] In some embodiments, Y is C(R.sup.2).sub.2, and R.sup.2 is
at least one hydrogen. In other embodiments R.sup.2 combine to form
.dbd.O, or each is independently optionally substituted
C.sub.1-C.sub.6 alkyl.
[0018] In certain embodiments, each of X.sup.2 and X.sup.9 is
independently CR.sup.1. In other embodiments, at least two R.sup.1
groups are --N(R.sup.3).sub.2.
[0019] In further embodiments, the compound has the structure of
formula (Ia):
##STR00003##
or a pharmaceutically acceptable salt thereof, where:
[0020] each R.sup.1 is independently halogen, hydroxyl, cyano,
nitro, --N(R.sup.3).sub.2, --S(O).sub.tR.sup.4, --OR.sup.3,
optionally substituted C.sub.1-C.sub.6 alkyl, optionally
substituted C.sub.6-C.sub.10aryl, optionally substituted
C.sub.3-C.sub.8cycloalkyl, or optionally substituted
heteroaryl.
[0021] In some embodiments, the compound has the structure of
formula (Ib):
##STR00004##
or a pharmaceutically acceptable salt thereof.
[0022] In certain embodiments, R.sup.2 is hydrogen, hydroxyl, or
optionally substituted C.sub.1-C.sub.6 alkyl.
[0023] In an aspect, the invention features a pharmaceutical
composition including a compound of formula (I):
##STR00005##
or a pharmaceutically acceptable salt thereof, where:
[0024] each of X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5,
X.sup.6, X.sup.7, X.sup.8, X.sup.9, and X.sup.10 is independently
CR.sup.1 or N;
[0025] Y is O, C(R.sup.2).sub.2, or S(O).sub.t;
[0026] each R.sup.1 is independently hydrogen, halogen, hydroxyl,
cyano, nitro, --N(R.sup.3).sub.2, --S(O).sub.tR.sup.4, --OR.sup.3,
optionally substituted C.sub.1-C.sub.6 alkyl, optionally
substituted C.sub.6-C.sub.10 aryl, optionally substituted
C.sub.3-C.sub.8 cycloalkyl, optionally substituted heteroaryl, or
optionally substituted heterocyclyl;
[0027] each R.sup.2 is independently hydrogen, hydroxyl, or
optionally substituted C.sub.1-C.sub.6alkyl; or both R.sup.2
combine to form .dbd.O, .dbd.S, or .dbd.NR.sup.5;
[0028] R.sup.3 is hydrogen, --SO.sub.2R.sup.4, optionally
substituted C.sub.1-C.sub.6 alkyl, optionally substituted
C.sub.6-C.sub.10 aryl, optionally substituted C.sub.3-C.sub.8
cycloalkyl, optionally substituted heteroaryl, or optionally
substituted heterocyclyl;
[0029] each R.sup.4 is independently optionally substituted
C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.6-C.sub.10
aryl, optionally substituted heteroaryl, or optionally substituted
heterocyclyl;
[0030] R.sup.5 is hydrogen, hydroxyl, --S(O).sub.2R.sup.4,
optionally substituted or C.sub.1-C.sub.6 alkyl; and each t is
independently 0, 1, or 2.
[0031] In certain embodiments, Y is C(R.sup.2).sub.2, and R.sup.2
is at least one hydrogen. In other embodiments, R.sup.2 combine to
form .dbd.O, or each is independently optionally substituted
C.sub.1-C.sub.6 alkyl.
[0032] In certain embodiments, each of X.sup.2 and X.sup.9 is
independently CR.sup.1. In other embodiments, at least two R.sup.1
groups are --N(R.sup.3).sub.2.
[0033] In further embodiments, the compound of a pharmaceutical
composition has the structure of formula (Ia):
##STR00006##
or a pharmaceutically acceptable salt thereof, where:
[0034] each R.sup.1 is independently halogen, hydroxyl, cyano,
nitro, --N(R.sup.3).sub.2, --S(O).sub.tR.sup.4, --OR.sup.3,
optionally substituted C.sub.1-C.sub.6 alkyl, optionally
substituted C.sub.6-C.sub.10aryl, optionally substituted
C.sub.3-C.sub.8cycloalkyl, or optionally substituted
heteroaryl.
[0035] In some embodiments, the compound of a pharmaceutical
composition has the structure of formula (Ib):
##STR00007##
or a pharmaceutically acceptable salt thereof.
[0036] In certain embodiments, R.sup.2 is hydrogen, hydroxyl, or
optionally substituted C.sub.1-C.sub.6 alkyl.
[0037] In some embodiments, the compound of formula (I) in a
pharmaceutical composition is selected from the group consisting
of:
##STR00008##
and pharmaceutically acceptable salts thereof.
[0038] In one aspect, the invention features a compound of formula
(II):
##STR00009##
or a pharmaceutically acceptable salt thereof, where:
[0039] (i) R.sup.1A and R.sup.1B combine to form .dbd.O, .dbd.S,
.dbd.C(R.sup.6).sub.2, or .dbd.NR.sup.7; R.sup.2A and R.sup.2B
combine to form .dbd.O, .dbd.S, .dbd.C(R.sup.6).sub.2, or
.dbd.NR.sup.7; and R.sup.3A and R.sup.3B, together with the atoms
to which they are attached, combine to form a double bond; or
[0040] (ii) each of R.sup.1A and R.sup.2A is independently
hydrogen, halogen, hydroxyl, cyano, nitro, --S(O).sub.tR.sup.6, or
--OR.sup.7; R.sup.1B and R.sup.3A, together with the atoms to which
they are attached, combine to form a double bond; and R.sup.2B and
R.sup.3B, together with the atoms to which they are attached,
combine to form a double bond;
[0041] both R.sup.4, together with the atoms to which they are
attached, combine to form an optionally substituted heterocyclic
ring;
[0042] both R.sup.5, together with the atoms to which they are
attached, combine to form an optionally substituted heterocyclic
ring;
[0043] each R.sup.6 is independently hydrogen, halogen, cyano, or
optionally substituted C.sub.1-C.sub.6 alkyl; each R.sup.7 is
independently hydroxyl, optionally substituted C.sub.1-C.sub.6
alkyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally
substituted C.sub.3-C.sub.8 cycloalkyl, optionally substituted
heteroaryl, or optionally substituted heterocyclyl; and
[0044] each t is independently 0, 1, or 2.
[0045] In some embodiments, the compound of formula (II) is not a
compound selected from the group consisting of:
##STR00010##
and pharmaceutically acceptable salts thereof.
[0046] In certain embodiments, both R.sup.4 together with the atoms
to which they are attached combine to form an optionally
substituted heterocyclic ring including an endocyclic nitrogen
atom. In other embodiments, both R.sup.4 together with the atoms to
which they are attached combine to form an optionally substituted
5-membered heterocyclic ring.
[0047] In some embodiments, both R.sup.5 together with the atoms to
which they are attached combine to form an optionally substituted
heterocyclic ring containing an endocyclic nitrogen atom. In
further embodiments, both R.sup.5 together with the atoms to which
they are attached combine to form an optionally substituted
5-membered heterocyclic ring.
[0048] In further embodiments, the compound has the structure of
formula (IIa):
##STR00011##
or a pharmaceutically acceptable salt thereof, and each R.sup.8 is
independently H or optionally substituted C.sub.1-C.sub.6
alkyl.
[0049] In some embodiments, R.sup.1A and R.sup.1B combine to form
.dbd.O. In some embodiments, R.sup.2A and R.sup.2B combine to form
.dbd.O. In particular embodiments, each of R.sup.1A and R.sup.2A is
independently hydrogen, halogen, or hydroxyl.
[0050] In an aspect, the invention features a pharmaceutical
composition including a compound of formula (II):
##STR00012##
or a pharmaceutically acceptable salt thereof, where:
[0051] (i) R.sup.1A and R.sup.1B combine to form .dbd.O, .dbd.S,
.dbd.C(R.sup.6).sub.2, or .dbd.NR.sup.7; R.sup.2A and R.sup.2B
combine to form .dbd.O, .dbd.S, .dbd.C(R.sup.6).sub.2, or
.dbd.NR.sup.7; and R.sup.3A and R.sup.3B, together with the atoms
to which they are attached, combine to form a double bond; or
[0052] (ii) each of R.sup.1A and R.sup.2A is independently
hydrogen, halogen, hydroxyl, cyano, nitro, --S(O)R.sup.6, or
--OR.sup.7; R.sup.1B and R.sup.3A, together with the atoms to which
they are attached, combine to form a double bond; and R.sup.2B and
R.sup.3B, together with the atoms to which they are attached,
combine to form a double bond; both R.sup.4, together with the
atoms to which they are attached, combine to form an optionally
substituted heterocyclic ring;
[0053] both R.sup.5, together with the atoms to which they are
attached, combine to form an optionally substituted heterocyclic
ring;
[0054] each R.sup.6 is independently hydrogen, halogen, cyano, or
optionally substituted C.sub.1-C.sub.6 alkyl; each R.sup.7 is
independently hydroxyl, optionally substituted C.sub.1-C.sub.6
alkyl, optionally substituted C.sub.6-C.sub.10 aryl, optionally
substituted C.sub.3-C.sub.8 cycloalkyl, optionally substituted
heteroaryl, or optionally substituted heterocyclyl; and each t is
independently 0, 1, or 2.
[0055] In certain embodiment, both R.sup.4 together with the atoms
to which they are attached combine to form an optionally
substituted heterocyclic ring including an endocyclic nitrogen
atom. In further embodiments, both R.sup.4 together with the atoms
to which they are attached combine to form an optionally
substituted 5-membered heterocyclic ring.
[0056] In particular embodiments, both R.sup.5 together with the
atoms to which they are attached combine to form an optionally
substituted heterocyclic ring containing an endocyclic nitrogen
atom. In other embodiments, both R.sup.5 together with the atoms to
which they are attached combine to form an optionally substituted
5-membered heterocyclic ring.
[0057] In further embodiments, the compound of a pharmaceutical
composition has the structure of formula (IIa):
##STR00013##
or a pharmaceutically acceptable salt thereof, and each R.sup.8 is
independently H or optionally substituted C.sub.1-C.sub.6
alkyl.
[0058] In some embodiments, R.sup.1A and R.sup.1B combine to form
.dbd.O. In some embodiments, R.sup.2A and R.sup.2B combine to form
.dbd.O. In particular embodiments, each of R.sup.1A and R.sup.2A is
independently hydrogen, halogen, or hydroxyl.
[0059] In some embodiments, the compound of formula (II) in a
pharmaceutical composition is selected from the group consisting
of:
##STR00014##
and pharmaceutically acceptable salts thereof.
[0060] In one aspect, the invention features a compound of formula
(III):
##STR00015##
or a pharmaceutically acceptable salt thereof, where:
[0061] R.sup.1 is an optionally substituted C.sub.6-C.sub.10 aryl
or optionally substituted heteroaryl;
[0062] each R.sup.2 is independently hydrogen or an optionally
substituted C.sub.1-C.sub.6 alkyl; and
[0063] In some embodiments, the compound of formula (III) is not a
compound selected from the group consisting of:
##STR00016##
and pharmaceutically acceptable salts thereof.
[0064] In some embodiments, R.sup.1 is optionally substituted
C.sub.6-C.sub.10 aryl. In certain embodiments, each R.sup.2 is
hydrogen.
[0065] In further embodiments, the compound has the structure of
formula (IIIa):
##STR00017##
or a pharmaceutically acceptable salt thereof, where:
[0066] R.sup.3 is optionally substituted C.sub.1-C.sub.6 alkyl,
halogen, --OR.sup.4, --S(O)R.sup.5, or --N(R.sup.4).sub.2;
[0067] each R.sup.4 is independently hydrogen or optionally
substituted C.sub.1-C.sub.6 alkyl;
[0068] R.sup.5 is optionally substituted C.sub.1-C.sub.6 alkyl,
optionally substituted C.sub.6-C.sub.10 aryl, or optionally
substituted heteroaryl; and
[0069] each t is independently 0, 1, or 2.
[0070] In particular embodiments, R.sup.3 is optionally substituted
C.sub.1-C.sub.6 alkyl or halogen.
[0071] In an aspect, the invention features a pharmaceutical
composition including a compound of formula (III):
##STR00018##
or a pharmaceutically acceptable salt thereof, where:
[0072] R.sup.1 is an optionally substituted C.sub.6-C.sub.10 aryl
or optionally substituted heteroaryl; and
[0073] each R.sup.2 is independently hydrogen or an optionally
substituted C.sub.1-C.sub.6 alkyl.
[0074] In some embodiments, R.sup.1 is optionally substituted
C.sub.6-C.sub.10 aryl. In certain embodiment, each R.sup.2 is
hydrogen.
[0075] In further embodiments, the compound of a pharmaceutical
composition has the structure of formula (IIIa):
##STR00019##
or a pharmaceutically acceptable salt thereof, where:
[0076] R.sup.3 is optionally substituted C.sub.1-C.sub.6 alkyl,
halogen, --OR.sup.4, --S(O)R.sup.5, or --N(R.sup.4).sub.2;
[0077] each R.sup.4 is independently hydrogen or optionally
substituted C.sub.1-C.sub.6 alkyl;
[0078] R.sup.5 is optionally substituted C.sub.1-C.sub.6 alkyl,
optionally substituted C.sub.6-C.sub.10 aryl, or optionally
substituted heteroaryl; and
[0079] each t is independently 0, 1, or 2.
[0080] In some embodiments, R.sup.3 is optionally substituted
C.sub.1-C.sub.6 alkyl, hydrogen, halogen, or cyano.
[0081] In particular embodiments, the compound of formula (III) of
a pharmaceutical composition is selected from the group consisting
of:
##STR00020##
and pharmaceutically acceptable salts thereof.
[0082] In one aspect, the disclosure features a method of
inhibiting interaction between IL18 and IL18R in a medium including
IL18 and a cell expressing IL18R by contacting the cell in the
medium with a compound disclosed herein. After the contacting step
the interaction between IL18 and IL18R is inhibited.
[0083] In some embodiments, the cell is in a subject. In some
embodiments, the medium is a tissue or bodily fluid of a
subject.
[0084] In another aspect, the disclosure features a method of
treating an inflammatory or autoimmune disorder in a subject in
need thereof by administering a therapeutically effective amount of
the compound disclosed herein, or a pharmaceutically acceptable
salt thereof, or the pharmaceutical composition disclosed herein to
the subject.
[0085] In some embodiments, the inflammatory or autoimmune disorder
is selected from the group consisting of rheumatoid arthritis,
osteoarthritis, lupus, renal disease, psoriasis, inflammatory bowel
disease, vascular graft failure, heart disease, vascular disease,
type 1 diabetes, type 2 diabetes, metabolic syndrome, diabetic
wound healing, and kidney disease. In certain embodiments, the
inflammatory or autoimmune disorder is a vascular graft failure. In
particular embodiments, the vascular graft failure is a peripheral
vascular graft failure. In further embodiments, the peripheral
vascular graft failure is a vein graft failure or prosthetic graft
failure. In yet further embodiments, the vascular graft failure is
a coronary artery graft failure. In still further embodiments, the
coronary graft failure is an is artery graft failure, vein graft
failure, prosthetic graft failure. In other embodiments, the
vascular graft failure is restenosis after stent graft. In yet
other embodiments, the vascular graft failure is restenosis after
balloon angioplasty. In still other embodiments, the inflammatory
or autoimmune disorder is a heart disease. In some embodiments, the
heart disease is cardiomyopathy, congestive heart failure, or
ischemic coronary heart disease. In certain embodiments, the
inflammatory or autoimmune disorder is a vascular disease. In
particular embodiments, the vascular disease is intimal
hyperplasia, atherosclerosis, coronary artery disease, restenosis,
primary hypertension, secondary hypertension, peripheral vascular
disease, or critical limb-threatening ischemia. In further
embodiments, the inflammatory or autoimmune disorder is type 1
diabetes, type 2 diabetes, metabolic syndrome, or diabetic wound
healing. In yet further embodiments, the inflammatory or autoimmune
disorder is a kidney disease. In still further embodiments, the
kidney disease is a chronic kidney disease, end-stage renal
disease, or kidney failure.
[0086] In some embodiments, the inflammatory or autoimmune disorder
is sepsis.
[0087] In some embodiments, the inflammatory or autoimmune disorder
is a cytokine storm.
[0088] In some embodiments, the inflammatory or autoimmune disorder
is endothelialitis. In some embodiments, the subject is suffering
from acute respiratory distress syndrome (ARDS) (e.g., ARDS
associated with an infection (e.g., a viral infection, such as a
beta-coronavirus infection or an influenza infection)). In some
embodiments, the inflammatory or autoimmune disorder is associated
with an infection (e.g., a viral infection, bacterian infection,
protozoan infection, or fungal infection). In some embodiments, the
inflammatory or autoimmune disorder is associated with a viremia.
In some embodiments, the inflammatory or autoimmune disorder is
associated with a bacteremia. In some embodiments, the inflammatory
or autoimmune disorder is associated with a protozoan infection. In
some embodiments, the inflammatory or autoimmune disorder is
associated with a fungal infection.
[0089] In some embodiments, the infection is a beta-coronavirus
infection. In some embodiments, the infection is SARS-CoV-2,
SARS-CoV, or MERS-CoV. In some embodiments, the infection is
SARS-CoV-2.
[0090] In some embodiments, the subject has been diagnosed with
SARS-CoV-2 infection.
[0091] In some embodiments, the subject has Covid-19 disease.
[0092] In some embodiments, the subject is an asymptomatic carrier
of SARS-CoV-2.
[0093] In some embodiments, the subject has one or more symptoms of
COVID-19 selected from the group consisting of fever, sore throat,
runny nose, sneezing, nasal congestion, snoring, coughing, dry
cough, shortness of breath, difficulty breathing, persistent pain
or pressure in the chest, dyspnea, pneumonia, acute respiratory
syndrome, cyanosis, myalgia, headache, encephalopathy, myocardial
injury, heart failure, arrhythmia, coagulation dysfunction, acute
kidney injury, confusion or inability to arouse, fatigue, and
gastrointestinal symptoms.
[0094] In some embodiments, the subject has suffered trauma (e.g.,
a blunt force trauma or a penetrating trauma).
[0095] In some embodiments, the subject has suffered burn
wounds.
[0096] In some embodiments, the subject has suffered Steven
Johnson's syndrome.
[0097] In some embodiments, the subject is concurrently treated
with assisted ventilation and oxygenation.
[0098] In some embodiments, the subject is concurrently treated
with an anti-viral drug.
[0099] In some embodiments, the antiviral agent is remdesivir,
chloroquine, hydroxychloroquine, baricitinib, lopinavir/ritonavir,
interferon beta, umifenovir, favipiravir, tocilizumab, or
ribavirin.
[0100] In some embodiments, the subject is concurrently treated
with an anti-inflammatory drug.
[0101] In some embodiments, the anti-inflammatory agent is
dexamethasone, celecoxib, diclofenac, difunisal, etodolac,
ibuprofen, indomethacin, ketoprofen, ketorolac, nabumetone,
naproxen, oxaprozin, prednisone, prednisolone, methylprednisolone,
or metformin.
[0102] In some embodiments, the subject is concurrently treated
with anti-coagulation drug.
[0103] In some embodiments, the anti-coagulation agent is tPA,
heparin, low molecular weight heparin, or bivalirudin.
[0104] In some embodiments, the subject has or is at risk of
developing acute respiratory distress syndrome, severe
cardiovascular damage, acute cardiac injury, acute kidney injury,
septic shock, multi-organ failure, and increased risk of death.
[0105] In some embodiments, the treatment of the invention
reverses, alleviates, ameliorates, inhibits, slows down, or stops
the progression or severity of one or more COVID-19 disease
symptom, e.g., as described herein.
[0106] In yet another aspect, the disclosure features a method of
treating a cancer in a subject in need thereof by administering a
therapeutically effective amount of the compound disclosed herein,
or a pharmaceutically acceptable salt thereof, or the
pharmaceutical composition disclosed herein to the subject.
[0107] In some embodiments, the cancer is gastric cancer, colon
cancer, melanoma, and multiple myeloma.
[0108] In another aspect, the invention can be used in the
treatment of a subject having sepsis, bacterial infection,
protozoan infection, fungal infection, viremia, bacteremia,
protozoan infection, or fungal infection
Definitions
[0109] The term "acyl," as used herein, represents a chemical
substituent of formula --C(O)--R, where R is alkyl, aryl,
arylalkyl, cycloalkyl, heterocyclyl, heterocyclyl alkyl,
heteroaryl, or heteroaryl alkyl. An optionally substituted acyl is
an acyl that is optionally substituted as described herein for each
group R.
[0110] The term "acyloxy," as used herein, represents a chemical
substituent of formula --OR, where R is acyl. An optionally
substituted acyloxy is an acyloxy that is optionally substituted as
described herein for acyl.
[0111] The term "alkanoyl," as used herein, represents a chemical
substituent of formula --C(O)--R, where R is alkyl. An optionally
substituted alkanoyl is an alknanoyl that is optionally substituted
as described herein for alkyl.
[0112] The term "alkoxy," as used herein, represents a chemical
substituent of formula --OR, where R is a C.sub.1-6 alkyl group,
unless otherwise specified. An optionally substituted alkoxy is an
alkoxy group that is optionally substituted as defined herein for
alkyl.
[0113] The term "alkyl," as used herein, refers to an acyclic
straight or branched chain saturated hydrocarbon group, which, when
unsubstituted, has from 1 to 12 carbons, unless otherwise
specified. In certain preferred embodiments, unsubstituted alkyl
has from 1 to 6 carbons. Alkyl groups are exemplified by methyl;
ethyl; n- and iso-propyl; n-, sec-, iso- and tert-butyl; neopentyl,
and the like, and may be optionally substituted, valency
permitting, with one, two, three, or, in the case of alkyl groups
of two carbons or more, four or more substituents independently
selected from the group consisting of: alkoxy; acyloxy; amino;
aryl; aryloxy; azido; cycloalkyl; cycloalkoxy; halo; heterocyclyl;
heteroaryl; heterocyclylalkyl; heteroarylalkyl; heterocyclyloxy;
heteroaryloxy; hydroxy; nitro; thiol; silyl; cyano; .dbd.O; .dbd.S;
and .dbd.NR', where R' is H, alkyl, aryl, or heterocyclyl. In some
embodiments, two substituents combine to form a group -L-CO--R,
where L is a bond or optionally substituted C.sub.1-.about.
alkylene, and R is hydroxyl or alkoxy. Each of the substituents may
itself be unsubstituted or, valency permitting, substituted with
unsubstituted substituent(s) defined herein for each respective
group.
[0114] The term "aryl," as used herein, represents a mono-,
bicyclic, or multicyclic carbocyclic ring system having one or two
aromatic rings. Aryl group may include from 6 to 10 carbon atoms.
All atoms within an unsubstituted carbocyclic aryl group are carbon
atoms. Non-limiting examples of carbocyclic aryl groups include
phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl,
fluorenyl, indanyl, indenyl, etc. The aryl group may be
unsubstituted or substituted with one, two, three, four, or five
substituents independently selected from the group consisting of:
alkyl; alkoxy; acyloxy; amino; aryl; aryloxy; azido; cycloalkyl;
cycloalkoxy; halo; heterocyclyl; heteroaryl; heterocyclylalkyl;
heteroarylalkyl; heterocyclyloxy; heteroaryloxy; hydroxy; nitro;
thiol; silyl; and cyano. Each of the substituents may itself be
unsubstituted or substituted with unsubstituted substituent(s)
defined herein for each respective group.
[0115] The term "aryl alkyl," as used herein, represents an alkyl
group substituted with an aryl group. The aryl and alkyl portions
may be optionally substituted as the individual groups as described
herein.
[0116] The term "aryloxy," as used herein, represents a group --OR,
where R is aryl. Aryloxy may be an optionally substituted aryloxy.
An optionally substituted aryloxy is aryloxy that is optionally
substituted as described herein for aryl.
[0117] The expression "C.sub.x-y," as used herein, indicates that
the group, the name of which immediately follows the expression,
when unsubstituted, contains a total of from x to y carbon atoms.
If the group is a composite group (e.g., aryl alkyl), C.sub.x,y
indicates that the portion, the name of which immediately follows
the expression, when unsubstituted, contains a total of from x to y
carbon atoms. For example, (C.sub.6-10-aryl)-C.sub.1-6-alkyl is a
group, in which the aryl portion, when unsubstituted, contains a
total of from 6 to 10 carbon atoms, and the alkyl portion, when
unsubstituted, contains a total of from 1 to 6 carbon atoms.
[0118] The term "cycloalkyl," as used herein, refers to a cyclic
alkyl group having from three to ten carbons (e.g., a
C.sub.3-C.sub.10 cycloalkyl), unless otherwise specified.
Cycloalkyl groups may be monocyclic or bicyclic. Bicyclic
cycloalkyl groups may be of bicyclo[p.q.0]alkyl type, in which each
of p and q is, independently, 1, 2, 3, 4, 5, 6, or 7, provided that
the sum of p and q is 2, 3, 4, 5, 6, 7, or 8. Alternatively,
bicyclic cycloalkyl groups may include bridged cycloalkyl
structures, e.g., bicyclo[p.q.r]alkyl, in which r is 1, 2, or 3,
each of p and q is, independently, 1, 2, 3, 4, 5, or 6, provided
that the sum of p, q, and r is 3, 4, 5, 6, 7, or 8. The cycloalkyl
group may be a spirocyclic group, e.g., spiro[p.q]alkyl, in which
each of p and q is, independently, 2, 3, 4, 5, 6, or 7, provided
that the sum of p and q is 4, 5, 6, 7, 8, or 9. Non-limiting
examples of cycloalkyl include cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, 1-bicyclo[2.2.1.]heptyl,
2-bicyclo[2.2.1.]heptyl, 5-bicyclo[2.2.1.]heptyl,
7-bicyclo[2.2.1.]heptyl, and decalinyl. The cycloalkyl group may be
unsubstituted or substituted (e.g., optionally substituted
cycloalkyl) with one, two, three, four, or five substituents
independently selected from the group consisting of: alkyl; alkoxy;
acyloxy; amino; aryl; aryloxy; azido; cycloalkyl; cycloalkoxy;
halo; heterocyclyl; heteroaryl; heterocyclylalkyl; heteroarylalkyl;
heterocyclyloxy; heteroaryloxy; hydroxy; nitro; thiol; silyl;
cyano; .dbd.O; .dbd.S; .dbd.NR', where R' is H, alkyl, aryl, or
heterocyclyl. Each of the substituents may itself be unsubstituted
or substituted with unsubstituted substituent(s) defined herein for
each respective group.
[0119] The term "cycloalkoxy," as used herein, represents a group
--OR, where R is cycloalkyl. Cycloalkoxy may be an optionally
substituted cycloalkoxy. An optionally substituted cycloalkoxy is
cycloalkoxy that is optionally substituted as described herein for
cycloalkyl.
[0120] The term "halo," as used herein, represents a halogen
selected from bromine, chlorine, iodine, and fluorine.
[0121] The term "heteroaryl," as used herein, represents a
monocyclic 5-, 6-, 7-, or 8-membered ring system, or a fused or
bridging bicyclic, tricyclic, or tetracyclic ring system; the ring
system contains one, two, three, or four heteroatoms independently
selected from the group consisting of nitrogen, oxygen, and sulfur;
and at least one of the rings is an aromatic ring. Non-limiting
examples of heteroaryl groups include benzimidazolyl, benzofuryl,
benzothiazolyl, benzothienyl, benzoxazolyl, furyl, imidazolyl,
indolyl, isoindazolyl, isoquinolinyl, isothiazolyl, isothiazolyl,
isoxazolyl, oxadiazolyl, oxazolyl, purinyl, pyrrolyl, pyridinyl,
pyrazinyl, pyrimidinyl, qunazolinyl, quinolinyl, thiadiazolyl
(e.g., 1,3,4-thiadiazole), thiazolyl, thienyl, triazolyl,
tetrazolyl, dihydroindolyl, tetrahydroquinolyl,
tetrahydroisoquinolyl, etc. The term bicyclic, tricyclic, and
tetracyclic heteroaryls include at least one ring having at least
one heteroatom as described above and at least one aromatic ring.
For example, a ring having at least one heteroatom may be fused to
one, two, or three carbocyclic rings, e.g., an aryl ring, a
cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a
cyclopentene ring, or another monocyclic heterocyclic ring.
Examples of fused heteroaryls include
1,2,3,5,8,8a-hexahydroindolizine; 2,3-dihydrobenzofuran;
2,3-dihydroindole; and 2,3-dihydrobenzothiophene. Heteroaryl may be
optionally substituted with one, two, three, four, or five
substituents independently selected from the group consisting of:
alkyl; alkoxy; acyloxy; aryloxy; amino; arylalkoxy; cycloalkyl;
cycloalkoxy; halogen; heterocyclyl; heterocyclyl alkyl; heteroaryl;
heteroaryl alkyl; heterocyclyloxy; heteroaryloxy; hydroxyl; nitro;
thiol; cyano; .dbd.O; --NR.sub.2, where each R is independently
hydrogen, alkyl, acyl, aryl, arylalkyl, cycloalkyl, heterocyclyl,
or heteroaryl; --COOR.sup.A, where R.sup.A is hydrogen, alkyl,
aryl, arylalkyl, cycloalkyl, heterocyclyl, or heteroaryl; and
--CON(R.sup.B).sub.2, where each R.sup.B is independently hydrogen,
alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, or heteroaryl.
Each of the substituents may itself be unsubstituted or substituted
with unsubstituted substituent(s) defined herein for each
respective group.
[0122] The term "heteroaryloxy," as used herein, refers to a
structure --OR, in which R is heteroaryl. Heteroaryloxy can be
optionally substituted as defined for heteroaryl.
[0123] The term "heterocyclyl," as used herein, represents a
monocyclic, bicyclic, tricyclic, or tetracyclic non-aromatic ring
system having fused or bridging 4-, 5-, 6-, 7-, or 8-membered
rings, unless otherwise specified, the ring system containing one,
two, three, or four heteroatoms independently selected from the
group consisting of nitrogen, oxygen, and sulfur. Non-aromatic
5-membered heterocyclyl has zero or one double bonds, non-aromatic
6- and 7-membered heterocyclyl groups have zero to two double
bonds, and non-aromatic 8-membered heterocyclyl groups have zero to
two double bonds and/or zero or one carbon-carbon triple bond.
Heterocyclyl groups have a carbon count of 1 to 16 carbon atoms
unless otherwise specified. Certain heterocyclyl groups may have a
carbon count up to 9 carbon atoms. Non-aromatic heterocyclyl groups
include pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl,
imidazolinyl, imidazolidinyl, piperidinyl, homopiperidinyl,
piperazinyl, pyridazinyl, oxazolidinyl, isoxazolidiniyl,
morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl,
thiazolidinyl, tetrahydrofuranyl, dihydrofuranyl,
tetrahydrothienyl, dihydrothienyl, pyranyl, dihydropyranyl,
dithiazolyl, etc. The term "heterocyclyl" also represents a
heterocyclic compound having a bridged multicyclic structure in
which one or more carbons and/or heteroatoms bridges two
non-adjacent members of a monocyclic ring, e.g., quinuclidine,
tropanes, or diaza-bicyclo[2.2.2]octane. The term "heterocyclyl"
includes bicyclic, tricyclic, and tetracyclic groups in which any
of the above heterocyclic rings is fused to one, two, or three
carbocyclic rings, e.g., a cyclohexane ring, a cyclohexene ring, a
cyclopentane ring, a cyclopentene ring, or another heterocyclic
ring. Examples of fused heterocyclyls include
1,2,3,5,8,8a-hexahydroindolizine; 2,3-dihydrobenzofuran;
2,3-dihydroindole; and 2,3-dihydrobenzothiophene. The heterocyclyl
group may be unsubstituted or substituted with one, two, three,
four or five substituents independently selected from the group
consisting of: alkyl; alkoxy; acyloxy; aryloxy; amino; arylalkoxy;
cycloalkyl; cycloalkoxy; halogen; heterocyclyl; heterocyclyl alkyl;
heteroaryl; heteroaryl alkyl; heterocyclyloxy; heteroaryloxy;
hydroxyl; nitro; thiol; cyano; .dbd.O; .dbd.S; --NR.sub.2, where
each R is independently hydrogen, alkyl, acyl, aryl, arylalkyl,
cycloalkyl, heterocyclyl, or heteroaryl; --COOR.sup.a, where
R.sup.a is hydrogen, alkyl, aryl, arylalkyl, cycloalkyl,
heterocyclyl, or heteroaryl; and --CON(R.sup.b).sub.2, where each
R.sup.b is independently hydrogen, alkyl, aryl, arylalkyl,
cycloalkyl, heterocyclyl, or heteroaryl.
[0124] The term "heterocyclyl alkyl," as used herein, represents an
alkyl group substituted with a heterocyclyl group. The heterocyclyl
and alkyl portions of an optionally substituted heterocyclyl alkyl
are optionally substituted as described for heterocyclyl and alkyl,
respectively.
[0125] The term "heterocyclyloxy," as used herein, refers to a
structure --OR, in which R is heterocyclyl. Heterocyclyloxy can be
optionally substituted as described for heterocyclyl.
[0126] The terms "hydroxyl" and "hydroxy," as used interchangeably
herein, represent --OH.
[0127] The term "oxo," as used herein, represents a divalent oxygen
atom (e.g., the structure of oxo may be shown as .dbd.O).
[0128] The term "pharmaceutically acceptable," as used herein,
refers to those compounds, materials, compositions, and/or dosage
forms, which are suitable for contact with the tissues of an
individual (e.g., a human), without excessive toxicity, irritation,
allergic response and other problem complications commensurate with
a reasonable benefit/risk ratio.
[0129] The term "protecting group," as used herein, represents a
group intended to protect a hydroxy, an amino, or a carbonyl from
participating in one or more undesirable reactions during chemical
synthesis.
[0130] The term "O-protecting group," as used herein, represents a
group intended to protect a hydroxy or carbonyl group from
participating in one or more undesirable reactions during chemical
synthesis. The term "N-protecting group," as used herein,
represents a group intended to protect a nitrogen containing (e.g.,
an amino or hydrazine) group from participating in one or more
undesirable reactions during chemical synthesis. Commonly used O-
and N-protecting groups are disclosed in Greene, "Protective Groups
in Organic Synthesis," 3.sup.rd Edition (John Wiley & Sons, New
York, 1999), which is incorporated herein by reference. Exemplary
O- and N-protecting groups include alkanoyl, aryloyl, or carbamyl
groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl,
2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl,
phthalyl, o-nitrophenoxyacetyl, .alpha.-chlorobutyryl, benzoyl,
4-chlorobenzoyl, 4-bromobenzoyl, t-butyldimethylsilyl,
tri-iso-propylsilyloxymethyl, 4,4'-dimethoxytrityl, isobutyryl,
phenoxyacetyl, 4-isopropylpehenoxyacetyl, dimethylformamidino, and
4-nitrobenzoyl.
[0131] Exemplary O-protecting groups for protecting carbonyl
containing groups include, but are not limited to: acetals,
acylals, 1,3-dithianes, 1,3-dioxanes, 1,3-dioxolanes, and
1,3-dithiolanes.
[0132] Other O-protecting groups include, but are not limited to:
substituted alkyl, aryl, and aryl-alkyl ethers (e.g., trityl;
methylthiomethyl; methoxymethyl; benzyloxymethyl; siloxymethyl;
2,2,2,-trichloroethoxymethyl; tetrahydropyranyl; tetrahydrofuranyl;
ethoxyethyl; 1-[2-(trimethylsilyl)ethoxy]ethyl;
2-trimethylsilylethyl; t-butyl ether; p-chlorophenyl,
p-methoxyphenyl, p-nitrophenyl, benzyl, p-methoxybenzyl, and
nitrobenzyl); silyl ethers (e.g., trimethylsilyl; triethylsilyl;
triisopropylsilyl; dimethylisopropylsilyl; t-butyldimethylsilyl;
t-butyldiphenylsilyl; tribenzylsilyl; triphenylsilyl; and
diphenymethylsilyl); carbonates (e.g., methyl, methoxymethyl,
9-fluorenylmethyl; ethyl; 2,2,2-trichloroethyl;
2-(trimethylsilyl)ethyl; vinyl, allyl, nitrophenyl; benzyl;
methoxybenzyl; 3,4-dimethoxybenzyl; and nitrobenzyl).
[0133] Other N-protecting groups include, but are not limited to,
chiral auxiliaries such as protected or unprotected D, L or D,
L-amino acids such as alanine, leucine, phenylalanine, and the
like; sulfonyl-containing groups such as benzenesulfonyl,
p-toluenesulfonyl, and the like; carbamate forming groups such as
benzyloxycarbonyl, p-chlorobenzyloxycarbonyl,
p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,
2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,
3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyl oxycarbonyl,
2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,
2-nitro-4,5-dimethoxybenzyloxycarbonyl,
3,4,5-trimethoxybenzyloxycarbonyl,
1-(p-biphenylyl)-1-methylethoxycarbonyl,
.alpha.,.alpha.-dimethyl-3,5-dimethoxybenzyloxycarbonyl,
benzhydryloxy carbonyl, t-butyloxycarbonyl,
diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl,
methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl,
phenoxycarbonyl, 4-nitrophenoxy carbonyl,
fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,
adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl,
and the like, aryl-alkyl groups such as benzyl, triphenylmethyl,
benzyloxymethyl, and the like and silyl groups such as
trimethylsilyl, and the like. Useful N-protecting groups are
formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl,
phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and
benzyloxycarbonyl (Cbz).
[0134] The term "subject," as used herein, represents a human or
non-human animal (e.g., a mammal) that is suffering from a disease
or condition, as determined by a qualified professional (e.g., a
doctor or a nurse practitioner) with or without known in the art
laboratory test(s) of sample(s) from the patient.
[0135] The term "treating," as used in reference to a disease or a
condition in a patient, is intended to refer to obtaining
beneficial or desired results, e.g., clinical results, in a patient
by administering a compound of the invention to the patient.
Beneficial or desired results may include alleviation or
amelioration of one or more symptoms of a disease or condition;
diminishment of extent of a disease or condition; stabilization
(i.e., not worsening) of a disease or condition; prevention of the
spread of a disease or condition; delay or slowing the progress of
a disease or condition; palliation of a disease or condition; and
remission (whether partial or total). "Palliating" a disease or
condition means that the extent and/or undesirable clinical
manifestations of the disease or condition are lessened and/or time
course of the progression is slowed, as compared to the extent or
time course in the absence of the treatment with the compound of
the invention. Non-limiting examples of diseases and conditions
that may be treated using compounds disclosed herein are
BRIEF DESCRIPTION OF THE DRAWINGS
[0136] FIG. 1A is a bar graph of HEK-Blue.TM. assay (HEK-IL-18
Sensor Cells): IL-18 activity assay for IL-18BP at different
concentrations (NT, 1.5 nM, 7.5 nM, and 37.5 nM).
[0137] FIG. 1B is a bar graph of HEK-Blue.TM. assay (HEK-IL-18
Sensor Cells): IL-18 activity assay for compound 1 at different
concentrations (NT, 1.5 nM, 7.5 nM, and 37.5 nM).
[0138] FIG. 1C is a bar graph of HEK-Blue.TM. assay (HEK-IL-18
Sensor Cells): IL-18 activity assay for compound 10 at different
concentrations (NT, 1.5 nM, 7.5 nM, and 37.5 nM).
[0139] FIG. 1D is a bar graph of HEK-Blue.TM. assay (HEK-IL-18
Sensor Cells): IL-18 activity assay for compound 15 at different
concentrations (NT, 1.5 nM, 7.5 nM, and 37.5 nM).
[0140] FIG. 2A is a bar graph of HEK-Blue SEAP reporter assay for
IL-18BP at low dose range (800 pM, 200 pM, 50 pM, 12.5 pM, and
NT).
[0141] FIG. 2B is a bar graph of HEK-Blue SEAP reporter assay for
compound 1 at low dose range (800 pM, 200 pM, 50 pM, 12.5 pM, and
NT).
[0142] FIG. 2C is a bar graph of HEK-Blue SEAP reporter assay for
compound 10 at low dose range (800 pM, 200 pM, 50 pM, 12.5 pM, and
NT).
[0143] FIG. 2D is a bar graph of HEK-Blue SEAP reporter assay for
compound 15 at low dose range (800 pM, 200 pM, 50 pM, 12.5 pM, and
NT).
[0144] FIG. 3A is a bar graph showing toxicity assay of compound 15
in Saphenous Vein Endothelial (EC) at different concentrations (10
nM, 100 nM, 1 .mu.M, and 10 .mu.M) and times (4, 28, and 76
hours).
[0145] FIG. 3B is a bar graph showing toxicity assay of compound 15
in Saphenous Vein Endothelial (EC) at different concentrations (10
nM, 100 nM, 1 .mu.M, and 10 .mu.M) and times (4, 28, and 76
hours).
[0146] FIG. 3C is a bar graph showing toxicity assay of compound 15
in Saphenous Vein Endothelial (EC) at different concentrations (10
nM, 100 nM, 1 .mu.M, and 10 .mu.M) and times (4, 28, and 76
hours).
[0147] FIG. 3D is a bar graph showing toxicity assay of compound 15
in Smooth Muscle Cells (SMC) at different concentrations (10 nM,
100 nM, 1 .mu.M, and 10 .mu.M) and times (4, 24, 28, 48, and 72
hours).
[0148] FIG. 3E is a bar graph showing toxicity assay of compound 15
in Smooth Muscle Cells (SMC) at different concentrations (10 nM,
100 nM, 1 .mu.M, and 10 .mu.M) and times (4, 24, 28, 48, and 72
hours).
[0149] FIG. 3F is a bar graph showing toxicity assay of compound 15
in Smooth Muscle Cells (SMC) at different concentrations (10 nM,
100 nM, 1 .mu.M, and 10 .mu.M) and times (24, 48, and 72
hours).
[0150] FIG. 4A is a bar graph depicting toxicity assay of compound
1 in Smooth Muscle Cells (SMC) at different concentrations (10 nM,
100 nM, 1 .mu.M and 10 .mu.M) and times (4, 24, 28, and 72
hours).
[0151] FIG. 4B is a bar graph depicting toxicity assay of compound
10 in Smooth Muscle Cells (SMC) at different concentrations (10 nM,
100 nM. 1 .mu.M and 10 .mu.M) and times (4, 24, 28, 72 hours).
[0152] FIG. 5 is a bar graph comparing Interferon-.gamma.
expression in NK92 cells of IL-18 and compounds 1V and 15.
[0153] FIG. 6 is a bar graph comparing Interferon-.gamma.
expression in NK92 cells of IL-18, compounds 1 and 1V.
[0154] FIG. 7 is a line graph comparing Microscale Thermophoresis
(MST) high binding affinity events of ligands (compounds 1 (top and
bottom lines) and 15 (middle line) with multiple affinities. FIG.
14 further depicts first phase of biphasic curves, occurring at low
ligand concentrations. Higher ligand concentrations are removed
from analysis and colored grey.
[0155] FIG. 8 is a line graph comparing MST low binding affinity
events of ligands (compounds 1 (top and bottom lines) and 15
(middle line)) with multiple affinities. FIG. 15 further depicts
second phase of biphasic curves, occurring at high ligand
concentrations. Lower ligand concentrations are removed from
analysis and colored grey.
[0156] FIG. 9A is a line graph comparing MST binding affinity
events of BP (top line) and compound 1 (bottom line) with multiple
affinities.
[0157] FIG. 9B is a line graph comparing MST binding affinity
events of BP (bottom line) and compound 10 (top line) with multiple
affinities.
[0158] FIG. 9C is a line graph comparing MST binding affinity
events of BP (bottom line) and compound 15 (top line) with multiple
affinities.
[0159] FIG. 10A is a bar graph showing cytokine levels in human
saphenous vein segments incubated with a control, LPS alone,
compound 1+LPS, compound 10+LPS, or compound 15+LPS.
[0160] FIG. 10B is a bar graph showing TNF-.alpha. levels in human
saphenous vein segments incubated with a control, LPS alone,
compound 1+LPS, compound 10+LPS, or compound 15+LPS.
[0161] FIG. 10C is a bar graph showing IL6 levels in human
saphenous vein segments incubated with a control, LPS alone,
compound 1+LPS, compound 10+LPS, or compound 15+LPS.
[0162] FIG. 10D is a bar graph showing IL8 levels in human
saphenous vein segments incubated with a control, LPS alone,
compound 1+LPS, compound 10+LPS, or compound 15+LPS.
DETAILED DESCRIPTION
[0163] In general, the invention provides compounds as described
herein, compositions including them, and methods of their use. The
compounds and compositions disclosed herein may be useful in the
treatment of an inflammatory or autoimmune disorder. For example,
the compounds and compositions disclosed herein may be useful in
the treatment of rheumatoid arthritis, osteoarthritis, lupus,
psoriasis, inflammatory bowel disease, vascular graft failure
(e.g., peripheral vascular graft failure, coronary artery graft
failure, restenosis after stent graft, or restenosis after balloon
angioplasty), heart disease (e.g., cardiomyopathy, congestive heart
failure, or ischemic coronary heart disease), vascular disease
(e.g., intimal hyperplasia, atherosclerosis, coronary artery
disease, restenosis, primary hypertension, secondary hypertension,
peripheral vascular disease, or critical limb-threatening
ischemia), type 1 diabetes, type 2 diabetes, metabolic syndrome,
diabetic wound healing, and kidney disease (e.g., chronic kidney
disease, end-stage renal disease, or kidney failure). The compounds
and compositions disclosed herein may also be useful in the
treatment of cancer (e.g., gastric cancer, colon cancer, melanoma,
or multiple myeloma).
[0164] Without wishing to be bound by theory, compounds disclosed
herein may inhibit interleukin-18 (IL18) and thus may be used in
the treatment of a disease or condition.
[0165] An IL18 inhibitor may be, e.g., a compound of formula
(I):
##STR00021##
or a pharmaceutically acceptable salt thereof, where:
[0166] each of X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5,
X.sup.6, X.sup.7, X.sup.8, X.sup.9, and X.sup.10 is independently
CR.sup.1 or N, provided that no more than two of X.sup.1, X.sup.2,
X.sup.3, X.sup.4, and X.sup.5 is N, and provided that no more than
two of X.sup.6, X.sup.7, X.sup.8, X.sup.9, and X.sup.10 is N;
[0167] Y is O, C(R.sup.2).sub.2, or S(O).sub.t;
[0168] each R.sup.1 is independently hydrogen, halogen, hydroxyl,
cyano, nitro, --N(R.sup.3).sub.2, --S(O).sub.tR.sup.4, --OR.sup.3,
optionally substituted C.sub.1-C.sub.6 alkyl, optionally
substituted C.sub.6-C.sub.10 aryl, optionally substituted
C.sub.3-C.sub.8 cycloalkyl, optionally substituted heteroaryl, or
optionally substituted heterocyclyl;
[0169] each R.sup.2 is independently hydrogen, hydroxyl, or
optionally substituted C.sub.1-C.sub.6alkyl; or both R.sup.2
combine to form .dbd.O, .dbd.S, or .dbd.NR.sup.5;
[0170] R.sup.3 is hydrogen, --SO.sub.2R.sup.4, optionally
substituted C.sub.1-C.sub.6 alkyl, optionally substituted
C.sub.6-C.sub.10 aryl, optionally substituted C.sub.3-C.sub.8
cycloalkyl, optionally substituted heteroaryl, or optionally
substituted heterocyclyl;
[0171] each R.sup.4 is independently optionally substituted
C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.6-C.sub.10
aryl, optionally substituted heteroaryl, or optionally substituted
heterocyclyl;
[0172] R.sup.5 is hydrogen, hydroxyl, --S(O).sub.2R.sup.4, or
optionally substituted or C.sub.1-C.sub.6 alkyl; and
[0173] each t is independently 0, 1, or 2.
[0174] In some embodiments, the compound of formula (I) is not a
compound selected from the group consisting of:
##STR00022##
and pharmaceutically acceptable salts thereof.
[0175] In some embodiments, the IL18 inhibitor is a compound of
formula (Ia):
##STR00023##
[0176] or a pharmaceutically acceptable salt thereof, wherein:
[0177] each R.sup.1 is independently halogen, hydroxyl, cyano,
nitro, --N(R.sup.3).sub.2, --S(O).sub.tR.sup.4, --OR.sup.3,
optionally substituted C.sub.1-C.sub.6 alkyl, optionally
substituted C.sub.6-C.sub.10aryl, optionally substituted
C.sub.3-C.sub.8cycloalkyl, or optionally substituted heteroaryl;
and
[0178] the remaining variables are as described for formula
(I).
[0179] In some embodiments, the IL18 inhibitor is a compound of
formula (Ib):
##STR00024##
[0180] or a pharmaceutically acceptable salt thereof, wherein all
variables are as described for formula (Ia).
[0181] An IL18 inhibitor may be, e.g., a compound of formula
(II):
##STR00025##
[0182] or pharmaceutically acceptable salts thereof, where:
[0183] (i) R.sup.1A and R.sup.1B combine to form .dbd.O, .dbd.S,
.dbd.C(R.sup.6).sub.2, or .dbd.NR.sup.7; R.sup.2A and R.sup.2B
combine to form .dbd.O, .dbd.S, .dbd.C(R.sup.6).sub.2, or
.dbd.NR.sup.7; and R.sup.3A and R.sup.3B, together with the atoms
to which they are attached, combine to form a double bond; or
[0184] (ii) each of R.sup.1A and R.sup.2A is independently
hydrogen, halogen, hydroxyl, cyano, nitro, --S(O).sub.tR.sup.6, or
--OR.sup.7; R.sup.1B and R.sup.3A, together with the atoms to which
they are attached, combine to form a double bond; and R.sup.2B and
R.sup.3B, together with the atoms to which they are attached,
combine to form a double bond;
[0185] both R.sup.4, together with the atoms to which they are
attached, combine to form an optionally substituted heterocyclic
ring;
[0186] both R.sup.5, together with the atoms to which they are
attached, combine to form an optionally substituted heterocyclic
ring;
[0187] each R.sup.6 is independently hydrogen, halogen, cyano, or
optionally substituted C.sub.1-C.sub.6 alkyl; and
[0188] each R.sup.7 is independently hydroxyl, optionally
substituted C.sub.1-C.sub.6 alkyl, optionally substituted
C.sub.6-C.sub.10 aryl, optionally substituted C.sub.3-C.sub.8
cycloalkyl, optionally substituted heteroaryl, or optionally
substituted heterocyclyl; and
[0189] each t is independently 0, 1, or 2.
[0190] In some embodiments, the compound of formula (II) is not a
compound selected from the group consisting of:
##STR00026##
and pharmaceutically acceptable salts thereof.
[0191] In some embodiments, the IL18 inhibitor is compound of
formula (IIa):
##STR00027##
[0192] or a pharmaceutically acceptable salts thereof, wherein:
[0193] each R.sup.8 is independently H or optionally substituted
C.sub.1-C.sub.6 alkyl; and
[0194] the remaining variables are as described for formulas
(II).
[0195] An IL18 inhibitor may be, e.g., a compound of formula
(III):
##STR00028##
[0196] or a pharmaceutically acceptable salt thereof, where:
[0197] R.sup.1 is an optionally substituted C.sub.6-C.sub.10 aryl
or optionally substituted heteroaryl; and
[0198] each R.sup.2 is independently hydrogen or an optionally
substituted C.sub.1-C.sub.6 alkyl.
[0199] In some embodiments, the compound of formula (III) is not a
compound selected from the group consisting of:
##STR00029##
and pharmaceutically acceptable salts thereof.
[0200] In some embodiments, the IL18 inhibitor is a compound of
formula (IIIa):
##STR00030##
[0201] or a pharmaceutically acceptable salt thereof,
[0202] where:
[0203] R.sup.3 is optionally substituted C.sub.1-C.sub.6 alkyl,
halogen, --OR.sup.4, --S(O).sub.tR.sup.5, or
--N(R.sup.4).sub.2;
[0204] each R.sup.4 is independently hydrogen or optionally
substituted C.sub.1-C.sub.6 alkyl;
[0205] R.sup.5 is optionally substituted C.sub.1-C.sub.6 alkyl,
optionally substituted C.sub.6-C.sub.10 aryl, or optionally
substituted heteroaryl.
[0206] Exemplary compounds are shown in Table 1.
TABLE-US-00001 TABLE 1 ##STR00031## 1 ##STR00032## 2 ##STR00033## 3
##STR00034## 4 ##STR00035## 5 ##STR00036## 6 ##STR00037## 7
##STR00038## 8 ##STR00039## 9 ##STR00040## 10 ##STR00041## 11
##STR00042## 12 ##STR00043## 13 ##STR00044## 14 ##STR00045## 15
##STR00046## 16 ##STR00047## 17 ##STR00048## 18 ##STR00049## 19
or a pharmaceutically acceptable salt of any of these
compounds.
[0207] A non-limiting example of a pharmaceutically acceptable salt
of a compound disclosed herein is:
##STR00050##
[0208] A non-limiting example of a pharmaceutically acceptable salt
of a compound disclosed herein is:
##STR00051##
[0209] A non-limiting example of a pharmaceutically acceptable salt
of a compound disclosed herein is:
##STR00052##
Methods of Use
[0210] The compounds disclosed herein may be used to inhibit the
interaction between IL18 and IL18R in a medium (e.g., a tissue or
bodily fluid of a subject) including IL18 and a cell expressing
IL18R. The methods typically include the step of contacting a
compound disclosed herein with the cell in the medium (by, e.g.,
administration to a subject including the cell). The contacting
step may result in inhibition of interaction between IL18 and
IL18R.
[0211] The compounds disclosed herein may be used in methods of
treating an inflammatory or autoimmune disorder in a subject in
need thereof. The methods typically include the step of
administering a therapeutically effective amount of the compounds
disclosed herein or a pharmaceutically acceptable salt thereof to
the subject. The compound or a pharmaceutically acceptable salt
thereof may be administered to the subject as a pharmaceutical
composition. The methods may be used to treat, e.g., rheumatoid
arthritis, osteoarthritis, lupus, psoriasis, inflammatory bowel
disease, vascular graft failure (e.g., peripheral vascular graft
failure, coronary artery graft failure, restenosis after stent
graft, or restenosis after balloon angioplasty), heart disease
(e.g., cardiomyopathy, congestive heart failure, or ischemic
coronary heart disease), vascular disease (e.g., intimal
hyperplasia, atherosclerosis, coronary artery disease, restenosis,
primary hypertension, secondary hypertension, peripheral vascular
disease, or critical limb-threatening ischemia), type 1 diabetes,
type 2 diabetes, metabolic syndrome, diabetic wound healing, and
kidney disease (e.g., chronic kidney disease, end-stage renal
disease, or kidney failure). Alternatively, the methods may be used
to treat, e.g., cancer (e.g., gastric cancer, colon cancer,
melanoma, or multiple myeloma), trauma, burn wounds, or Steven
Johnsons Syndrome.
[0212] The compounds described herein may be used in the treatment
of an infection (e.g., a viral infection, such as a
beta-coronavirus infection or an influenza infection). The
compounds described herein may be used in the treatment of a viral
infection, bacterian infection, protozoan infection, or fungal
infection. The subject may be suffering from, e.g., acute
respiratory distress syndrome (ARDS) (e.g., ARDS associated with an
infection (e.g., a viral infection, such as a beta-coronavirus
infection or an influenza infection)). The compounds described
herein may be used, e.g., to treat a cytokine storm or
endothelialitis (e.g., vascular endothelialitis). Infections (e.g.,
beta-coronavirus infections (e.g., SARS-CoV-2)) may lead to severe
vascular dysfunction (e.g., vascular endothelialitis) and/or
thromboinflammation. Eventually, the infections (e.g.,
beta-coronavirus infections (e.g., SARS-CoV-2)) may lead, e.g., to
microvascular thrombi, which, in turn may lead to lung failure. The
cytokine storm or endotheliitis may be, e.g., associated with an
infection (e.g., a viral infection (e.g., a beta-coronavirus
infection)). The infection may be, e.g., SARS-CoV-2, SARS-CoV, or
MERS-CoV. Preferably, the infection is SARS-CoV-2. The subject may
be, e.g., one that has been diagnosed with SARS-CoV-2 infection.
The subject may have, e.g., COVID-19. The subject may be, e.g., an
asymptomatic carrier of a beta-coronavirus (e.g., SARS-CoV-2).
Alternatively, the subject may have one or more symptoms of
COVID-19, e.g., fever, sore throat, runny nose, sneezing, nasal
congestion, snoring, coughing, dry cough, shortness of breath,
difficulty breathing, persistent pain or pressure in the chest,
dyspnea, pneumonia, acute respiratory syndrome, cyanosis, myalgia,
headache, encephalopathy, myocardial injury, heart failure,
arrhythmia, coagulation dysfunction, acute kidney injury, confusion
or inability to arouse, fatigue, or gastrointestinal symptoms. The
subject may have or may be at risk of, e.g., developing acute
respiratory distress syndrome, severe cardiovascular damage, acute
cardiac injury, acute kidney injury, septic shock, multi-organ
failure, or increased risk of death. The compounds and methods of
the invention may reverse, alleviate, ameliorate, inhibit, slow
down, or stop the progression or severity of one or more COVID-19
disease symptom, e.g., as described herein.
[0213] The subject may also be treated with, e.g., assisted
ventilation or oxygenation. For example, the subject is
concurrently treated with assisted ventilation and oxygenation. The
subject may also be treated with an anti-viral drug. For example,
the subject is concurrently treated with an anti-viral drug.
Non-limiting examples of anti-viral drugs include remdesivir,
chloroquine, hydroxychloroquine, baricitinib, lopinavir/ritonavir,
interferon beta, umifenovir, favipiravir, tocilizumab, and
ribavirin. The subject may also be treated with an
anti-inflammatory drug. For example, the subject is concurrently
treated with an anti-inflammatory drug. Non-limiting examples of
anti-inflammatory drugs include dexamethasone, celecoxib,
diclofenac, difunisal, etodolac, ibuprofen, indomethacin,
ketoprofen, ketorolac, nabumetone, naproxen, oxaprozin, prednisone,
prednisolone, methylprednisolone, and metformin. The subject may
also be treated with an anti-coagulation drug. For example, the
subject is concurrently treated with an anti-coagulation drug.
Non-limiting examples of anti-coagulation drugs include, tPA,
heparin, low molecular weight heparin, bivalirudin, aspirin.
[0214] Exemplary routes of administration of the compounds (e.g., a
compound of the invention), or pharmaceutical compositions thereof,
used in the present invention include oral, sublingual, buccal,
transdermal, intradermal, intramuscular, parenteral, intravenous,
intra-arterial, intracranial, subcutaneous, intraorbital,
intraventricular, intraspinal, intraperitoneal, intranasal,
inhalation, and topical administration.
Methods of Preparing Compounds
[0215] The compounds disclosed herein can be prepared by processes
analogous to those established in the art, for example, by the
reaction sequence shown in scheme 1. The numbering system used for
the general schemes does not necessarily correspond to that
employed elsewhere in the description or in the claims.
[0216] As shown in scheme 1, one strategy to access compound (3A)
is to subject compound (2A) to alkylation, acylation, or
sulfonylation reaction conditions. Compounds of invention (2A) may
be obtained in two steps from compounds of the invention (1A) first
nitration reaction, followed with the reduction of the nitro
groups.
##STR00053##
[0217] Compound (1A) may be prepared using techniques and methods
known in the art (Scheme 2), e.g. oxidation of compound 5A, a
Friedel-Crafts alkylation reaction product of compound 4A and
compound 4B, or Friedel-Crafts acylation reaction of compound 4A
and acyl chloride 6A using strong Lewis acids (e.g. AlCl.sub.3,
FeCl.sub.3 or MX.sub.n reagents). Friedel-Crafts alkylation
reactions utilizing benzyl alcohol as an electrophile proceed via a
benzylic carbocation formed in situ from its ionization in the
presence of an acid having strong ionizing and poor nucleophilic
properties (e.g. TFA).
##STR00054##
[0218] As shown in scheme 3, compounds of invention (8A) may be
accessed using techniques and method known in the art, e.g.,
reduction of carbonyl moiety to alkane. Non-limiting examples of
the reduction reactions include Clemmensen reduction and
Wolff-Kishner reduction. Typically, Clemmensen reduction utilizes
zinc (e.g., zinc amalgam) under acidic conditions (e.g., conc. aq.
HCl). Wolff-Kishner reduction typically involves thermolysis of
hydrazones obtained from hydrazine and a ketone (e.g., compound
2A). Compound (8A) may be directly obtain from the reduction of the
carbonyl moiety in compound (3A) or alternatively through
alkylation, acylation or sulfonylation of compound of invention
(7A), which in turn may be access upon reduction of ketone moiety
in compound (2A).
##STR00055##
[0219] One skilled in the art would know that the carbonyl moiety
in compound (3A) may be functionalized using appropriate reaction
conditions to allow the preparation of compounds of invention
(9A-10A and 12A-13A), scheme 4: condensation with an amine may give
compound of the invention (9A); reaction with mild thionating
reagents such as Lawesson's reagent may yield compound of the
invention (10A); Grignard reaction may generate secondary alcohol
30, which may be activated into a good leaving group (e.g.
O-triflate, I or Br) and subsequently reacted with a nucleophile to
provide compound of the invention (12A); 1,2-reduction (e.g. using
sodium borohydride as a reducing agent) may provide compound of the
invention (13A).
##STR00056##
[0220] Compounds of the invention (18A) may be prepared via
alkylation, acylation or sulfonylation of compound (17A). Compound
(17A) may be obtained from the reduction of the nitro groups in
compound (16A), which is the oxidative product of the sulfur moiety
in compound (15A). Condensation of compound 14A with sodium sulfide
may provide compound (15A).
##STR00057##
[0221] One method to access compounds of the invention (23A) is
through the alkylation, acylation or sulfonylation of compound
(22A), scheme 6. Reduction of the nitro group in compound (21A)
(e.g. using SnCl.sub.2) may result in compound (22A). This in turn
may be obtain from O-arylation reaction of compound 19A and
compound 20A.
##STR00058##
[0222] It is known in the art that dipolar cycloaddition reaction
of compound 24A and azides may yield compounds of the invention
(25A), scheme 7. Subjecting compound (25A) under applicable
reaction conditions may give access to respective compounds of this
invention: reaction with amines may yield compounds of the
invention (26A); reacting with Lawesson's reagent may give
compounds of the invention (27A); may be converted to compounds of
the invention (28A) by reacting with ammonium hydroxide in the
presence of pyridine in ethanol; Knoevenagel condensation reaction
with malononitrile in the presence of a base may result in
compounds of the invention (29A).
##STR00059##
[0223] One option to obtain compound of the invention (31A) as
shown in scheme 8 is to react compound 30A with sodium nitrite in
the presence of bromic acid. Alkylation reaction following standard
protocols (e.g., using base such as K.sub.2CO.sub.2,
Cs.sub.2CO.sub.3) may yield compound (32A), an advance intermediate
to prepare other compounds of this invention: copper-catalyzed
Ullmann amination reaction conditions may provide compounds of the
invention (33A) (e.g., compound (33A), where R.sup.7 is H may be
further reacted under Sandmeyer reaction conditions to give
compounds of the invention (34A)); Grignard reaction may give
compounds of the invention (54A); Pd-catalyzed nitration reaction
may allow access to compounds of the invention (36A).
##STR00060##
[0224] Compounds of the invention (39A) may be achieved from
NMP-catalyzed condensation of compound 37A and compound 38A (Scheme
9). Bromination of compound (39A) may give compound (40A), which
may be subjected to proper reaction conditions as describe in
scheme 8 to access compounds of the invention (41A), (42A), (43A),
and (44A).
##STR00061##
[0225] One approach to access compounds of the invention (47A) is
the condensation of compound 45A and compound 46A (e.g., using
tosylic acid monohydrate and copper iodide as co-catalyst) (Scheme
10). Bromination of compound (47A) may provide compound (48A),
which when subjected to appropriate reaction conditions as describe
in scheme 8 may give access to compounds of the invention (49A),
(50A), (51A), and (52A).
##STR00062##
[0226] As shown in scheme 11, one strategy to synthesize compounds
of the invention (55A) is to utilize known procedures in the art of
amine 54A nucleophilic addition to electrophile (dicyandiamide
53A). To facilitate access to more substituted compounds of
invention (61A), dicyandiamide derivatives 60A may reacted with
amine 54A as shown in scheme 12.
##STR00063##
[0227] Compound 60A may be prepared according to known procedures
in the art. The reaction of amine 56A with isothiocynate 57A
(prepared from reacting carbon disulfide with amine 56A) may yield
thiourea 58A, which upon reacting with methyl iodide may give salt
59A. Desulfurylation of compound 59A with cyanamide may yield
compound 60A.
##STR00064##
[0228] In the reactions described above, it may be necessary to
protect reactive functional groups (e.g., hydroxyl, amino, thio, or
carboxyl groups) to avoid their unwanted participation in the
reactions. The incorporation of such groups, and the methods
required to introduce and remove them are known to those skilled in
the art (for example, Greene). The deprotection step may be the
final step in the synthesis such that the removal of protecting
groups affords compounds of formula (I), (Ia), (Ib), (II), (IIa),
(III), or (IIIa) as disclosed herein. Starting materials used in
any of the schemes above can be purchased or prepared by methods
described in the chemical literature, or by adaptations thereof,
using methods known by those skilled in the art. The order in which
the steps are performed can vary depending on the groups introduced
and the reagents used, but would be apparent to those skilled in
the art.
[0229] Compounds of any of formula (I), (Ia), (Ib), (II), (IIa),
(III), or (IIIa), or any of the intermediates described in the
schemes above, can be further derivatized by using one or more
standard synthetic methods describe herein or known to those
skilled in the art. Such methods can involve substitution,
oxidation or reduction reactions. These methods can also be used to
obtain or modify compounds of formula (I), (Ia), (Ib), (II), (IIa),
(III), or (IIIa), or any preceding intermediates by modifying,
introducing or removing appropriate functional groups. Particular
substitution approaches include alkylation, arylation,
heteroarylation, acylation, thioacylation, halogenation,
sulfonylation, nitration, formylation, hydrolysis, and coupling
procedures. These procedures can be used to introduce a functional
group onto the parent molecule (e.g., the nitration or
sulfonylation of aromatic rings) or to couple two molecules
together (for example to couple an amine to a carboxylic acid to
afford an amide; or to form a carbon-carbon bond between two
heterocycles). For example, alcohol or phenol groups can be
converted to ether groups by coupling a phenol with an alcohol in a
solvent, e.g., tetrahydrofuran in the presence of a phosphine
(e.g., triphenylphosphine) and a dehydrating agent (e.g., diethyl-,
diisopropyl-, or dimethylazodicarboxylate). Alternatively, ether
groups can be prepared by deprotonation of an alcohol, using a
suitable base (e.g., sodium hydride) followed by the addition of an
alkylating agent (e.g., an alkyl halide or an alkylsulfonate).
[0230] In another example, --OH groups may be generated from the
corresponding ester, acid, acid chloride or aldehyde by reduction
with a suitable reducing agent, e.g., a complex metal hydride,
e.g., lithium aluminum hydride in a solvent (e.g.,
tetrahydrofuran).
[0231] In another example, hydroxyl groups (including phenolic OH
groups) can be converted into leaving groups, e.g., halogen atoms
or sulfonyloxy groups (e.g., alkylsulfonyloxy, e.g.,
trifluoromethylsulfonyloxy, or arylsufonyl, e.g.,
p-toluenesulfonyloxy) using conditions known to those skilled in
the art. For example, an aliphatic alcohol can be reacted with
thionyl chloride in a halogenated hydrocarbon (e.g.,
dichloromethane) to afford the corresponding alkylchloride. A base
(e.g., triethylamine) can also be used in the reaction.
[0232] In another example, ester groups can be converted to the
corresponding carboxylic acid by acid- or base-catalyzed hydrolysis
depending on the nature of the ester group. Acid catalysed
hydrolysis can be achieved by treatment with an organic or
inorganic acid (e.g., trifluoroacetic acid in an aqueous solvent,
or a mineral acid, e.g., hydrochloric acid in a solvent, e.g.,
dioxan). Base catalyzed hydrolysis can be achieved by treatment
with an alkali metal hydroxide (e.g., lithium hydroxide in an
aqueous alcohol, e.g., methanol).
[0233] In another example, aromatic halogen substituents in the
compounds may be subjected to halogen-metal exchange by treatment
with a base (e.g., a lithium base, e.g., n-butyl or t-butyl
lithium) optionally at a low temperature (e.g., -78.degree. C.) in
a solvent (e.g., tetrahydrofuran) and the mixture may then quenched
with an electrophile to introduce a desired substituent. Thus, for
example, a formyl group can be introduced by using
dimethylformamide as the electrophile. Aromatic halogen
substituents can also be subjected to palladium catalyzed reactions
to introduce groups, e.g., carboxylic acids, esters, cyano, or
amino substituents.
[0234] In another example, aromatic halogen substituents in the
compounds may participate in a range of metal catalyzed reactions
to introduce alternative functional groups, e.g., amines, amides,
ethers, thiols, aryl groups, or heteroaryl groups.
[0235] Particular oxidation approaches include dehydrogenations and
aromatization, and the addition of oxygen to certain functional
groups. For example, aldehyde groups can be prepared by oxidation
of the corresponding alcohol using conditions well known to those
skilled in the art. For example, an alcohol can be treated with an
oxidizing agent (e.g., the Dess-Martin reagent) in a solvent (e.g.,
a halogenated hydrocarbon, for example dichloromethane).
Alternative oxidizing conditions can be used, e.g., treatment with
oxalyl chloride and an activating amount of dimethylsulfoxide and
subsequent quenching by the addition of an amine (e.g.,
triethylamine). Such a reaction can be carried out in an
appropriate solvent (e.g., a halogenated hydrocarbon, for example
dichloromethane) and under appropriate conditions (e.g., cooling
below room temperature, e.g., to -78.degree. C. followed by warming
to room temperature). In another example, sulphur atoms can be
oxidized to the corresponding sulfoxide or sulfone using an
oxidizing agent (e.g., a peroxy acid, e.g., 3-chloroperoxybenzoic
acid) in an inert solvent (e.g., a halogenated hydrocarbon, e.g.,
dichloromethane) at around ambient temperature.
[0236] Particular reduction approaches include the removal of
oxygen atoms from particular functional groups, saturation (or
partial saturation) of unsaturated compounds including aromatic
rings. For example, primary alcohols can be generated from the
corresponding ester or aldehyde by reduction, using a metal hydride
(e.g., lithium aluminum hydride or sodium borohydride in a solvent,
e.g., methanol).
[0237] Alternatively, --OH groups can be generated from the
corresponding carboxylic acid by reduction, using a metal hydride
(e.g., lithium aluminum hydride in a solvent, e.g.,
tetrahydrofuran). In another example, a nitro group may be reduced
to an amine by catalytic hydrogenation in the presence of a metal
catalyst (e.g., palladium on a solid support, e.g., carbon) in a
solvent (e.g., an ether, e.g., tetrahydrofuran, or an alcohol,
e.g., methanol), or by chemical reduction using a metal (e.g., tin
or iron) in the presence of an acid (e.g., hydrochloric acid). In a
further example an amine can be obtained by reduction of a nitrile,
e.g., by catalytic hydrogenation in the presence of a metal
catalyst (e.g., palladium on a solid support, e.g., carbon), or
Raney nickel in a solvent (e.g., tetrahydrofuran) and under
suitable conditions (e.g., cooling to below room temperature, e.g.,
to -78.degree. C., or heating, e.g., to reflux).
Pharmaceutical Compositions
[0238] The compounds used in the methods described herein are
preferably formulated into pharmaceutical compositions for
administration to human subjects in a biologically compatible form
suitable for administration in vivo. Pharmaceutical compositions
typically include a compound as described herein and a
pharmaceutically acceptable excipient.
[0239] The compounds described herein can also be used in the form
of the free base, in the form of salts, zwitterions, solvates, or
as prodrugs, or pharmaceutical compositions thereof. All forms are
within the scope of the invention. The compounds, salts,
zwitterions, solvates, prodrugs, or pharmaceutical compositions
thereof, may be administered to a patient in a variety of forms
depending on the selected route of administration, as will be
understood by those skilled in the art. The compounds used in the
methods described herein may be administered, for example, by oral,
parenteral, buccal, sublingual, nasal, rectal, patch, pump, or
transdermal administration, and the pharmaceutical compositions
formulated accordingly. Parenteral administration includes
intravenous, intraperitoneal, subcutaneous, intramuscular,
transepithelial, nasal, intrapulmonary, intrathecal, rectal, and
topical modes of administration. Parenteral administration may be
by continuous infusion over a selected period of time.
[0240] For human use, a compound of the invention can be
administered alone or in admixture with a pharmaceutical carrier
selected with regard to the intended route of administration and
standard pharmaceutical practice. Pharmaceutical compositions for
use in accordance with the present invention thus can be formulated
in a conventional manner using one or more physiologically
acceptable carriers comprising excipients and auxiliaries that
facilitate processing of a compound of the invention into
preparations which can be used pharmaceutically.
[0241] This invention also includes pharmaceutical compositions
which can contain one or more pharmaceutically acceptable carriers.
In making the pharmaceutical compositions of the invention, the
active ingredient is typically mixed with an excipient, diluted by
an excipient or enclosed within such a carrier in the form of, for
example, a capsule, sachet, paper, or other container. When the
excipient serves as a diluent, it can be a solid, semisolid, or
liquid material (e.g., normal saline), which acts as a vehicle,
carrier or medium for the active ingredient. Thus, the compositions
can be in the form of tablets, powders, lozenges, sachets, cachets,
elixirs, suspensions, emulsions, solutions, syrups, and soft and
hard gelatin capsules. As is known in the art, the type of diluent
can vary depending upon the intended route of administration. The
resulting compositions can include additional agents, e.g.,
preservatives.
[0242] The excipient or carrier is selected on the basis of the
mode and route of administration. Suitable pharmaceutical carriers,
as well as pharmaceutical necessities for use in pharmaceutical
formulations, are described in Remington: The Science and Practice
of Pharmacy, 21.sup.st Ed., Gennaro, Ed., Lippincott Williams &
Wilkins (2005), a well-known reference text in this field, and in
the USP/NF (United States Pharmacopeia and the National Formulary).
Examples of suitable excipients are lactose, dextrose, sucrose,
sorbitol, mannitol, starches, gum acacia, calcium phosphate,
alginates, tragacanth, gelatin, calcium silicate, microcrystalline
cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and
methyl cellulose. The formulations can additionally include:
lubricating agents, e.g., talc, magnesium stearate, and mineral
oil; wetting agents; emulsifying and suspending agents; preserving
agents, e.g., methyl- and propylhydroxy-benzoates; sweetening
agents; and flavoring agents. Other exemplary excipients are
described in Handbook of Pharmaceutical Excipients, 6.sup.th
Edition, Rowe et al., Eds., Pharmaceutical Press (2009).
[0243] These pharmaceutical compositions can be manufactured in a
conventional manner, e.g., by conventional mixing, dissolving,
granulating, dragee-making, levigating, emulsifying, encapsulating,
entrapping, or lyophilizing processes. Methods well known in the
art for making formulations are found, for example, in Remington:
The Science and Practice of Pharmacy, 21.sup.st Ed., Gennaro, Ed.,
Lippincott Williams & Wilkins (2005), and Encyclopedia of
Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan,
1988-1999, Marcel Dekker, New York. Proper formulation is dependent
upon the route of administration chosen. The formulation and
preparation of such compositions is well-known to those skilled in
the art of pharmaceutical formulation. In preparing a formulation,
the active compound can be milled to provide the appropriate
particle size prior to combining with the other ingredients. If the
active compound is substantially insoluble, it can be milled to a
particle size of less than 200 mesh. If the active compound is
substantially water soluble, the particle size can be adjusted by
milling to provide a substantially uniform distribution in the
formulation, e.g., about 40 mesh.
Dosages
[0244] The dosage of the compound used in the methods described
herein, or pharmaceutically acceptable salts or prodrugs thereof,
or pharmaceutical compositions thereof, can vary depending on many
factors, e.g., the pharmacodynamic properties of the compound; the
mode of administration; the age, health, and weight of the
recipient; the nature and extent of the symptoms; the frequency of
the treatment, and the type of concurrent treatment, if any; and
the clearance rate of the compound in the animal to be treated. One
of skill in the art can determine the appropriate dosage based on
the above factors. The compounds used in the methods described
herein may be administered initially in a suitable dosage that may
be adjusted as required, depending on the clinical response. In
general, a suitable daily dose of a compound of the invention will
be that amount of the compound that is the lowest dose effective to
produce a therapeutic effect. Such an effective dose will generally
depend upon the factors described above.
[0245] A compound of the invention may be administered to the
patient in a single dose or in multiple doses. When multiple doses
are administered, the doses may be separated from one another by,
for example, 1-24 hours, 1-7 days, 1-4 weeks, or 1-12 months. The
compound may be administered according to a schedule or the
compound may be administered without a predetermined schedule. An
active compound may be administered, for example, 1, 2, 3, 4, 5, 6,
7, 8, 9, 10, 11, or 12 times per day, every 2.sup.nd, 3.sup.rd,
4.sup.th, 5.sup.th, or 6.sup.th day, 1, 2, 3, 4, 5, 6, or 7 times
per week, 1, 2, 3, 4, 5, or 6 times per month, or 1, 2, 3, 4, 5, 6,
7, 8, 9, 10, 11, or 12 times per year. It is to be understood that,
for any particular subject, specific dosage regimes should be
adjusted overtime according to the individual need and the
professional judgment of the person administering or supervising
the administration of the compounds or compositions.
[0246] While the attending physician ultimately will decide the
appropriate amount and dosage regimen, an effective amount of a
compound of the invention may be, for example, a total daily dosage
of, e.g., between 0.05 mg and 3000 mg of any of the compounds
described herein. Alternatively, the dosage amount can be
calculated using the body weight of the patient. Such dose ranges
may include, for example, between 10-1000 mg (e.g., 50-800 mg). In
some embodiments, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500,
550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of the
compound is administered.
[0247] In the methods of the invention, the time period during
which multiple doses of a compound of the invention are
administered to a patient can vary. For example, in some
embodiments doses of the compounds of the invention are
administered to a patient over a time period that is 1-7 days; 1-12
weeks; or 1-3 months. In other embodiments, the compounds are
administered to the patient over a time period that is, for
example, 4-11 months or 1-30 years. In other embodiments, the
compounds are administered to a patient at the onset of symptoms.
In any of these embodiments, the amount of compound that is
administered may vary during the time period of administration.
When a compound is administered daily, administration may occur,
for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times per
day.
Formulations
[0248] A compound identified as capable of treating any of the
conditions described herein, using any of the methods described
herein, may be administered to patients or animals with a
pharmaceutically-acceptable diluent, carrier, or excipient, in unit
dosage form. The chemical compounds for use in such therapies may
be produced and isolated by any standard technique known to those
in the field of medicinal chemistry. Conventional pharmaceutical
practice may be employed to provide suitable formulations or
compositions to administer the identified compound to patients
suffering from a bacterial infection. Administration may begin
before the patient is symptomatic.
[0249] Exemplary routes of administration of the compounds (e.g., a
compound of the invention), or pharmaceutical compositions thereof,
used in the present invention include oral, sublingual, buccal,
transdermal, intradermal, intramuscular, parenteral, intravenous,
intra-arterial, intracranial, subcutaneous, intraorbital,
intraventricular, intraspinal, intraperitoneal, intranasal,
inhalation, and topical administration. The compounds desirably are
administered with a pharmaceutically acceptable carrier.
Pharmaceutical formulations of the compounds described herein
formulated for treatment of the disorders described herein are also
part of the present invention.
Formulations for Oral Administration
[0250] The pharmaceutical compositions contemplated by the
invention include those formulated for oral administration ("oral
dosage forms"). Oral dosage forms can be, for example, in the form
of tablets, capsules, a liquid solution or suspension, a powder, or
liquid or solid crystals, which contain the active ingredient(s) in
a mixture with non-toxic pharmaceutically acceptable excipients.
These excipients may be, for example, inert diluents or fillers
(e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline
cellulose, starches including potato starch, calcium carbonate,
sodium chloride, lactose, calcium phosphate, calcium sulfate, or
sodium phosphate); granulating and disintegrating agents (e.g.,
cellulose derivatives including microcrystalline cellulose,
starches including potato starch, croscarmellose sodium, alginates,
or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol,
acacia, alginic acid, sodium alginate, gelatin, starch,
pregelatinized starch, microcrystalline cellulose, magnesium
aluminum silicate, carboxymethylcellulose sodium, methylcellulose,
hydroxypropyl methylcellulose, ethylcellulose,
polyvinylpyrrolidone, or polyethylene glycol); and lubricating
agents, glidants, and antiadhesives (e.g., magnesium stearate, zinc
stearate, stearic acid, silicas, hydrogenated vegetable oils, or
talc). Other pharmaceutically acceptable excipients can be
colorants, flavoring agents, plasticizers, humectants, buffering
agents, and the like.
[0251] Formulations for oral administration may also be presented
as chewable tablets, as hard gelatin capsules wherein the active
ingredient is mixed with an inert solid diluent (e.g., potato
starch, lactose, microcrystalline cellulose, calcium carbonate,
calcium phosphate or kaolin), or as soft gelatin capsules wherein
the active ingredient is mixed with water or an oil medium, for
example, peanut oil, liquid paraffin, or olive oil. Powders,
granulates, and pellets may be prepared using the ingredients
mentioned above under tablets and capsules in a conventional manner
using, e.g., a mixer, a fluid bed apparatus or a spray drying
equipment.
[0252] Controlled release compositions for oral use may be
constructed to release the active drug by controlling the
dissolution and/or the diffusion of the active drug substance. Any
of a number of strategies can be pursued in order to obtain
controlled release and the targeted plasma concentration versus
time profile. In one example, controlled release is obtained by
appropriate selection of various formulation parameters and
ingredients, including, e.g., various types of controlled release
compositions and coatings. Examples include single or multiple unit
tablet or capsule compositions, oil solutions, suspensions,
emulsions, microcapsules, microspheres, nanoparticles, patches, and
liposomes. In certain embodiments, compositions include
biodegradable, pH, and/or temperature-sensitive polymer
coatings.
[0253] Dissolution or diffusion controlled release can be achieved
by appropriate coating of a tablet, capsule, pellet, or granulate
formulation of compounds, or by incorporating the compound into an
appropriate matrix. A controlled release coating may include one or
more of the coating substances mentioned above and/or, e.g.,
shellac, beeswax, glycowax, castor wax, carnauba wax, stearyl
alcohol, glyceryl monostearate, glyceryl distearate, glycerol
palmitostearate, ethylcellulose, acrylic resins, dl-polylactic
acid, cellulose acetate butyrate, polyvinyl chloride, polyvinyl
acetate, vinyl pyrrolidone, polyethylene, polymethacrylate,
methylmethacrylate, 2-hydroxymethacrylate, methacrylate hydrogels,
1,3 butylene glycol, ethylene glycol methacrylate, and/or
polyethylene glycols. In a controlled release matrix formulation,
the matrix material may also include, e.g., hydrated
methylcellulose, carnauba wax and stearyl alcohol, carbopol 934,
silicone, glyceryl tristearate, methyl acrylate-methyl
methacrylate, polyvinyl chloride, polyethylene, and/or halogenated
fluorocarbon.
[0254] The liquid forms in which the compounds and compositions of
the present invention can be incorporated for administration orally
include aqueous solutions, suitably flavored syrups, aqueous or oil
suspensions, and flavored emulsions with edible oils, e.g.,
cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as
elixirs and similar pharmaceutical vehicles.
Formulations for Buccal Administration
[0255] Dosages for buccal or sublingual administration typically
are 0.1 to 500 mg per single dose as required. In practice, the
physician determines the actual dosing regimen which is most
suitable for an individual patient, and the dosage varies with the
age, weight, and response of the particular patient. The above
dosages are exemplary of the average case, but individual instances
exist wherein higher or lower dosages are merited, and such are
within the scope of this invention.
[0256] For buccal administration, the compositions may take the
form of tablets, lozenges, etc. formulated in a conventional
manner. Liquid drug formulations suitable for use with nebulizers
and liquid spray devices and electrohydrodynamic (EHD) aerosol
devices will typically include a compound of the invention with a
pharmaceutically acceptable carrier. Preferably, the
pharmaceutically acceptable carrier is a liquid, e.g., alcohol,
water, polyethylene glycol, or a perfluorocarbon. Optionally,
another material may be added to alter the aerosol properties of
the solution or suspension of compounds of the invention.
Desirably, this material is liquid, e.g., an alcohol, glycol,
polyglycol, or a fatty acid. Other methods of formulating liquid
drug solutions or suspension suitable for use in aerosol devices
are known to those of skill in the art (see, e.g., Biesalski, U.S.
Pat. No. 5,112,598 and Biesalski, U.S. Pat. No. 5,556,611, each of
which is herein incorporated by reference).
Formulations for Nasal or Inhalation Administration
[0257] The compounds may also be formulated for nasal
administration. Compositions for nasal administration also may
conveniently be formulated as aerosols, drops, gels, and powders.
The formulations may be provided in a single or multidose form. In
the case of a dropper or pipette, dosing may be achieved by the
patient administering an appropriate, predetermined volume of the
solution or suspension. In the case of a spray, this may be
achieved, for example, by means of a metering atomizing spray
pump.
[0258] The compounds may further be formulated for aerosol
administration, particularly to the respiratory tract by inhalation
and including intranasal administration. The compound will
generally have a small particle size for example on the order of
five (5) microns or less. Such a particle size may be obtained by
means known in the art, for example by micronization. The active
ingredient is provided in a pressurized pack with a suitable
propellant, e.g., a chlorofluorocarbon (CFC), for example,
dichlorodifluoromethane, trichlorofluoromethane, or
dichlorotetrafluoroethane, or carbon dioxide, or other suitable
gas. The aerosol may conveniently also contain a surfactant, e.g.,
lecithin. The dose of drug may be controlled by a metered valve.
Alternatively, the active ingredients may be provided in a form of
a dry powder, e.g., a powder mix of the compound in a suitable
powder base, e.g., lactose, starch, and starch derivatives, e.g.,
hydroxypropylmethyl cellulose, and polyvinylpyrrolidine (PVP). The
powder carrier will form a gel in the nasal cavity. The powder
composition may be presented in unit dose form for example in
capsules or cartridges of e.g., gelatin or blister packs from which
the powder may be administered by means of an inhaler.
[0259] Aerosol formulations typically include a solution or fine
suspension of the active substance in a physiologically acceptable
aqueous or non-aqueous solvent and are usually presented in single
or multidose quantities in sterile form in a sealed container,
which can take the form of a cartridge or refill for use with an
atomizing device. Alternatively, the sealed container may be a
unitary dispensing device, e.g., a single dose nasal inhaler or an
aerosol dispenser fitted with a metering valve which is intended
for disposal after use. Where the dosage form comprises an aerosol
dispenser, it will contain a propellant, which can be a compressed
gas, e.g., compressed air or an organic propellant, e.g.,
fluorochlorohydrocarbon. The aerosol dosage forms can also take the
form of a pump-atomizer.
Formulations for Parenteral Administration
[0260] The compounds described herein for use in the methods of the
invention can be administered in a pharmaceutically acceptable
parenteral (e.g., intravenous or intramuscular) formulation as
described herein. The pharmaceutical formulation may also be
administered parenterally (intravenous, intramuscular, subcutaneous
or the like) in dosage forms or formulations containing
conventional, non-toxic pharmaceutically acceptable carriers and
adjuvants. In particular, formulations suitable for parenteral
administration include aqueous and non-aqueous sterile injection
solutions which may contain anti-oxidants, buffers, bacteriostats
and solutes which render the formulation isotonic with the blood of
the intended recipient; and aqueous and non-aqueous sterile
suspensions which may include suspending agents and thickening
agents. For example, to prepare such a composition, the compounds
of the invention may be dissolved or suspended in a parenterally
acceptable liquid vehicle. Among acceptable vehicles and solvents
that may be employed are water, water adjusted to a suitable pH by
addition of an appropriate amount of hydrochloric acid, sodium
hydroxide or a suitable buffer, 1,3-butanediol, Ringer's solution
and isotonic sodium chloride solution. The aqueous formulation may
also contain one or more preservatives, for example, methyl, ethyl,
or n-propyl p-hydroxybenzoate. Additional information regarding
parenteral formulations can be found, for example, in the United
States Pharmacopeia-National Formulary (USP-NF), herein
incorporated by reference.
[0261] The parenteral formulation can be any of the five general
types of preparations identified by the USP-NF as suitable for
parenteral administration: [0262] (1) "Drug Injection:" a liquid
preparation that is a drug substance (e.g., a compound of the
invention), or a solution thereof; [0263] (2) "Drug for Injection:"
the drug substance (e.g., a compound of the invention) as a dry
solid that will be combined with the appropriate sterile vehicle
for parenteral administration as a drug injection; [0264] (3) "Drug
Injectable Emulsion:" a liquid preparation of the drug substance
(e.g., a compound of the invention) that is dissolved or dispersed
in a suitable emulsion medium; [0265] (4) "Drug Injectable
Suspension:" a liquid preparation of the drug substance (e.g., a
compound of the invention) suspended in a suitable liquid medium;
and [0266] (5) "Drug for Injectable Suspension:" the drug substance
(e.g., a compound of the invention) as a dry solid that will be
combined with the appropriate sterile vehicle for parenteral
administration as a drug injectable suspension.
[0267] Exemplary formulations for parenteral administration include
solutions of the compound prepared in water suitably mixed with a
surfactant, e.g., hydroxypropylcellulose. Dispersions can also be
prepared in glycerol, liquid polyethylene glycols, DMSO and
mixtures thereof with or without alcohol, and in oils.
[0268] Under ordinary conditions of storage and use, these
preparations may contain a preservative to prevent the growth of
microorganisms. Conventional procedures and ingredients for the
selection and preparation of suitable formulations are described,
for example, in Remington: The Science and Practice of Pharmacy,
21.sup.st Ed., Gennaro, Ed., Lippincott Williams & Wilkins
(2005) and in the United States Pharmacopeia: the National
Formulary (USP 36 NF31), published in 2013.
[0269] Formulations for parenteral administration may, for example,
contain excipients, sterile water, or saline, polyalkylene glycols,
e.g., polyethylene glycol, oils of vegetable origin, or
hydrogenated napthalenes. Biocompatible, biodegradable lactide
polymer, lactide/glycolide copolymer, or
polyoxyethylene-polyoxypropylene copolymers may be used to control
the release of the compounds. Other potentially useful parenteral
delivery systems for compounds include ethylene-vinyl acetate
copolymer particles, osmotic pumps, implantable infusion systems,
and liposomes. Formulations for inhalation may contain excipients,
for example, lactose, or may be aqueous solutions containing, for
example, polyoxyethylene-9-lauryl ether, glycocholate and
deoxycholate, or may be oily solutions for administration in the
form of nasal drops, or as a gel.
[0270] The parenteral formulation can be formulated for prompt
release or for sustained/extended release of the compound.
Exemplary formulations for parenteral release of the compound
include: aqueous solutions, powders for reconstitution, cosolvent
solutions, oil/water emulsions, suspensions, oil-based solutions,
liposomes, microspheres, and polymeric gels.
[0271] The following examples are meant to illustrate the
invention. They are not meant to limit the invention in any
way.
EXAMPLES
Example 1. In Vitro Assays of the Compounds
[0272] Small Inhibitor Compound Preparation
[0273] Inhibitor compounds were solubilized and stored in DMSO at
stock concentrations between 2.5-250 mM. Structure of compounds
assayed are shown in Table 2.
TABLE-US-00002 TABLE 2 ##STR00065## 1 ##STR00066## 10 ##STR00067##
15 ##STR00068## 1V
[0274] HEK-Blue IL18 Cell Reporter Assay
[0275] HEK-Blue IL18 Cells (Invivogen California, USA), are a
derivative of HEK293 cells that have been stably transfected with
IL18R.alpha./IL18RAP genes and a SEAP reporter gene that is
expressed and secreted in specific response to IL18. Cells were
grown in 25 mm.sup.2 tissue culture flasks with DMEM culture medium
containing 4.5 g/L glucose, 10% (v/v) heat-inactivated fetal bovine
serum, 50 .mu./mL penicillin, 50 .mu.g/mL streptomycin, 100
.mu.g/mL Normocin and 2 mM L-glutamine at 37.degree. C. in 5%
CO.sub.2.
[0276] Stock concentration of IL18 was 750 .mu.M stored in Tris-HCl
buffer at -80.degree. C. For treatment use, compounds were diluted
in sterile PBS to 100 times the intended treatment concentration
and administered into wells containing 198 .mu.l media at volumes
of 2 .mu.l. Total DMSO contents for all vehicles was less than
0.02% prior to treatment, and less than 0.0002% within wells
following treatment.
[0277] HEK-Blue IL18 cells were transferred from flasks and seeded
at 40-50% confluency on 96-well culture plates 6 hours prior to
treatment.
[0278] Phase I: Cells were treated with compounds at concentrations
of 3.75 nM, 7.5 pM, and 1.5 pM, with three replicate wells for each
concentration, and six replicate wells with no compound treatment
(NT). All wells were then immediately co-treated with recombinant
human IL18 at one concentration between 15 pM-100 pM. Following
treatments, cells were incubated at 37.degree. C. in 5% CO.sub.2
for 18 hours. Cell confluency typically reached 70-80%
(.about.80,000-100,000 cells per well) by this point, 24 hours
after seeding. IL18BP and compounds 1, 10, and 15 all significantly
reduce IL-18 activity, see FIGS. 1A-1D respectively.
[0279] Phase II: Six Most potent inhibitory compounds were tested
with the following protocol: six replicate wells treated with a
selected compound at a low dose range (800 pM, 200 pM, 50 pM, 12.5
pM, NT, plus 50 pM IL18 co-treatment) and a higher dose range (1600
pM, 400 pM, 100 pM, 25 pM, NT, plus 100 pM IL18 treatment).
[0280] To detect SEAP activity, 20 .mu.L supernatant from each well
was transferred and mixed with 180 .mu.l alkaline phosphatase
detection medium (QUANTi-Blue, InvivoGen, California, USA), in a
separate 96-well plate and incubated for 3 hours at room
temperature. Supernatant SEAP activity was measured by reading the
optical density (OD) at 640 nm using a spectrophotometer. OD values
were standardized to NT mean=1.
[0281] Statistical analysis was performed GraphPad Prism
(California, USA) software. One-Way analysis of variance (ANOVA)
with Dunnett's post-hoc analysis was used to determine significant
variation between treatment and control (NT) groups treated only
with IL18. IL18BP and compounds 1, 10, and 15 induction of SEAP
production results are shown in FIGS. 2A-2D respectively.
[0282] Alamar Blue Assay for Cell Toxicity and Proliferation
[0283] Compounds that tested positive in the HEK Blue Assay were
subjected to cell toxicity and proliferation assay using Alamar
Blue. Primary human saphenous vein smooth muscle (SMC) and
endothelial cells (EC) were left untreated or treated with
inhibitor compounds (10 nM-10 .mu.M) for a period of 3-4 days. Cell
proliferation was measured using our previously published Alamar
Blue Assay (Monahan et al., FASEB J., 23:557-564, 2009; Yoshida et
al., J. Am. Coll. Surg. 213:668-67, 2011).
[0284] In these assays compound 15 showed no toxicity up to 76
hours in EC (see FIGS. 3A-3C) and up to 72 hours in SMC (see FIGS.
3D-3F). Compounds 1 and 10 also showed no toxicity up to 72 hours
in SMC (see FIGS. 4A and 4B respectively).
[0285] IFN-.gamma. Gene Expression Induction in NK-92 Cells
[0286] IFN-.gamma. gene and protein expression induction is a
standard to measure IL-18 activity in NK92 cells (Kalina et al., J.
Immunol. 165:1307-1313, 2000).
[0287] NK92 cells were treated with 1 .mu.M concentration of
compounds 1, 10, or 1V. Compound 1V is a known inhibitor of
IFN-.gamma. expression in NK92 cells (Kalina et al., J. Immunol.
2000 165, 1307-1313). 24 hours after treatment, total RNA was
harvested and qRT-PCR was conducted using a previously published
protocols (Raof et al., BMC Genomics, 17-20, 2016; Monahan et al.,
FASEB J., 23:557-564, 2009) to measure the gene expression of
IFN-.gamma.. Comparison of the ligand-induced IFN-.gamma.
expression is shown in FIG. 5: IL-18 significantly increases
IFN-.gamma. expression (5.52.+-.3.43) vs. no treatment
(1.06.+-.0.38); compound 15 (1 .mu.M) significantly decreases
IFN-.gamma. expression (0.99.+-.0.38) vs. IL-18 treated cells. FIG.
6 shows IFN-.gamma. expression inhibition results: IL-18
significantly increases IFN-.gamma. expression (7.9.+-.7.23) vs. no
treatment (1.33.+-.0.85); compound 1 (1 .mu.M) significantly
decreases IFN-.gamma. expression (0.04.+-.0.02) vs. IL-18 treated
cells; 1V is a positive control and a known IFN-.gamma. expression
inhibitor.
Microscale Thermophoresis
[0288] Recombinant IL18 was fluorescently labelled using the lysine
reactive Pico RED NT647 dye from NanoTemper Technologies and stored
in a PBS buffer containing 0.05% TWEEN (Buffer A). Stock
concentration of labelled IL18 was 10 M. Working concentrations of
IL18 were diluted in Buffer A to 10, 40, or 50 nM. Except for the
positive control, IL18BP, stock concentration for all compounds, or
ligands, was 10-25 mM in 100% DMSO. Ligands were diluted in Buffer
A to working concentrations of 50-500 .mu.M. Containing 0.8-2%
DMSO. Stock concentration of IL8BP, was 50 .mu.M, stored in 20 mM
Tris-HI buffer (pH 8.0) containing 0.4 M Urea and 10% glycerol
(Buffer B). Prior to MST experiments being performed 16
preparations of two-fold serial dilutions of ligand in uniform
buffer, starting with the working Uigand concentration, were
incubated with equal volumes of a fixed concentration of labelled
IL8. After 30 minutes incubation at room temperature, 16 Monolith
NT. 15 standard capillaries were loaded with 10 .mu.l volumes of
each of the ligand/IL18 preparations. Tests described in Results
were run at 3700.
[0289] Experiments were performed on a Monolith NT.115Pico machine
(NanoTemper Technologies GmbH, Germany). Data quality and analysis
and graphic rendering were performed using MO.Affinity Analysis
v2.3 software from NanoTemper technologies. Evaluation strategy for
all analyses was standardized to measure relative change of
fluorescence (FNorm %) over a 2.5 second of laser induced
temperature shift per capillary. Statistical analysis was performed
using NanoTemper's MOControl software. The results of this assay
for compounds 1, 10, and 15 are shown in FIGS. 7, 8, 9A, 9B, and 90
and Table 3 describes the MST assay conditions.
TABLE-US-00003 TABLE 3 Name: IL18BP 1 10 15 Target Name: IL18 IL18
IL18 IL18 Target Concentration: 5 nM 20 nM 20 nM 20 nM Ligand Name:
BP CP1 CP10 CP15 Ligand Concentration 25 .mu.M to 100 .mu.M to 100
.mu.M to 100 .mu.M to 0.000763 .mu.M 0.00305 .mu.uM 0.00305 .mu.M
0.00305 .mu.M n: 2 2 2 2 Comments: Excitation Power: 20% 5% 5% 5%
MST Power: 40% 40% 40% 40% Temperature: 37.0.degree. C.
37.0.degree. C. 37.0.degree. C. 37.0.degree. C. Kd: 1.8469E-09
6.0575E-08 2.2711E-09 5.6441E-06 Kd Confidence: .+-.1.0427E-09
.+-.6.8251E-08 .+-.4.1613E-09 .+-.2.7051E-06 Response Amplitude:
4.9133364 6.2004726 5.5261596 7.07334911 TargetConc: 5E-09[Fixed]
1.3693E-15 5E-09[Fixed] 2E-08[Fixed] Unbound: 871.43 867.62 881.12
872.28 Bound: 866.52 861.42 875.59 865.21 Std. Error of Regression:
0.52447759 1.0917105 1.3511843 0.98154729 Reduced X.sup.2:
20.871973 13.716328 10.456252 144.08809 Signal to Noise: 10.062908
6.4074464 4.3932183 7.7408351
[0290] FIG. 9A is graph showing binding affinity events of BP
(Kd=1.85 nM; Kd Conf.+-.1.04 nM) and compound 1 (Kd=60.6 nM; Kd
Conf.+-.68.3 nM). FIG. 9B is graph illustrating binding affinity
events of BP (Kd=1.85 nM; Kd Conf.+-.1.04 nM) and compound 10
(Kd=2.27 nM; Kd Conf.+-.4.16 nM). FIG. 90 is graph illustrating
binding affinity events of BP (Kd=1.85 nM; Kd Conf.+-.1.04 nM) and
compound 15 (Kd=5.60 .mu.M; Kd Conf.+-.2.71 .mu.M). For all three
compounds high affinity binding events occur at low ligand
concentration, and low affinity binding events also appear to occur
at higher ligand concentrations.
Example 2. Cytokine Expression in Human Saphenous Vein Ex Vivo
[0291] In this example, a cytokine storm/inflammation common to
many vascular conditions has been modeled by challenging human
saphenous vein segments with lipopolysaccharide (LPS). Discarded
human saphenous vein samples were collected from patients
undergoing peripheral bypass grafting.
[0292] Samples were subjected to Human (h) TheRPA (Therapeutic
Responses Predictor Assay) which is based on ex-vivo treatment of
biopsies (explant cultures). The tissues were transferred to the
lab within 30 min of their harvesting and cultured in DMEM+10%
FBS+1% antibiotic/antimycotic (DMEM plus glucose, glutamine, sodium
pyruvate: Gibco 11995-065; Heat Inactivated FBS: Gibco 16140-089;
Antibiotic-Antimycotic: Gibco 15240-096) in the presence of
vehicle, LPS (100 ng/ml) or LPS (100 ng/ml)+compound 1/compound
10/compound 15 (10 .mu.M). After 18 hours, culture supernatants
were collected and kept at -80.degree. C. Cytokine levels in cell
culture supernatant were measured by multiplex ELISA (Milliplex map
human cytokine/chemokine magnetic bead kit from Millipore). The
results of this test are shown in FIGS. 10A-10D. Compounds 1, 5,
and 10 all significantly inhibited IL-6, IL-8 and TNF expression.
Additionally, all three compounds also inhibited the endogenous
expression of other cytokines including IFN-.gamma., IL-13, and
IL-2.
Other Embodiments
[0293] Various modifications and variations of the described
invention will be apparent to those skilled in the art without
departing from the scope and spirit of the invention. Although the
invention has been described in connection with specific
embodiments, it should be understood that the invention as claimed
should not be unduly limited to such specific embodiments. Indeed,
various modifications of the described modes for carrying out the
invention that are obvious to those skilled in the art are intended
to be within the scope of the invention.
[0294] Some embodiments are within the scope of the following
enumerated paragraphs:
1. A compound of formula (I):
##STR00069##
or a pharmaceutically acceptable salt thereof, wherein:
[0295] each of X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5,
X.sup.6, X.sup.7, X.sup.8, X.sup.9, and X.sup.10 is independently
CR.sup.1 or N;
[0296] Y is O, C(R.sup.2).sub.2, or S(O).sub.t;
[0297] each R.sup.1 is independently hydrogen, halogen, hydroxyl,
cyano, nitro, --N(R.sup.3).sub.2, --S(O).sub.tR.sup.4, --OR.sup.3,
optionally substituted C.sub.1-C.sub.6 alkyl, optionally
substituted C.sub.6-C.sub.10 aryl, optionally substituted
C.sub.3-C.sub.8 cycloalkyl, optionally substituted heteroaryl, or
optionally substituted heterocyclyl;
[0298] each R.sup.2 is independently hydrogen or optionally
substituted C.sub.1-C.sub.6 alkyl; or both R.sup.2 combine to form
.dbd.O, .dbd.S, or .dbd.NR.sup.5;
[0299] R.sup.3 is hydrogen, --SO.sub.2R.sup.4, optionally
substituted C.sub.1-C.sub.6 alkyl, optionally substituted
C.sub.6-C.sub.10 aryl, optionally substituted C.sub.3-C.sub.8
cycloalkyl, optionally substituted heteroaryl, or optionally
substituted heterocyclyl;
[0300] each R.sup.4 is independently optionally substituted
C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.6-C.sub.10
aryl, optionally substituted heteroaryl, or optionally substituted
heterocyclyl;
[0301] R.sup.5 is hydrogen, hydroxyl, --S(O).sub.2R.sup.4, or
optionally substituted C.sub.1-C.sub.6 alkyl;
[0302] each t is independently 0, 1, or 2; and
the compound of formula (I) is not a compound selected from the
group consisting of:
##STR00070##
and pharmaceutically acceptable salts thereof; and provided that at
least one of X.sup.1, X.sup.2, X.sup.3, X.sup.4, and X.sup.5 is
CR.sup.1, at least one of X.sup.6, X.sup.7, X.sup.8, X.sup.9, and
X.sup.10 is CR.sup.1, and at least one R.sup.1 is halogen,
hydroxyl, cyano, nitro, --N(R.sup.3).sub.2, --S(O).sub.tR.sup.4,
--OR.sup.3, or optionally substituted C.sub.1-C.sub.6 alkyl. 2. The
compound of paragraph 1, wherein Y is C(R.sup.2).sub.2. 3. The
compound of paragraph 1 or 2, wherein at least one R.sup.2 is
hydrogen. 4. The compound of paragraph 1 or 2, wherein both R.sup.2
combine to form .dbd.O. 5. The compound of paragraph 1 or 2,
wherein each R.sup.2 is independently optionally substituted
C.sub.1-C.sub.6alkyl. 6. The compound of any one of paragraphs 1 to
5, wherein each of X.sup.2 and X.sup.9 is independently CR.sup.1.
7. The compound of any one of paragraphs 1 to 6, wherein at least
two R.sup.1 groups are --N(R.sup.3).sub.2. 8. The compound of
paragraph 1, wherein the compound is a compound of formula
(Ia):
##STR00071##
or a pharmaceutically acceptable salt thereof, wherein:
[0303] each R.sup.1 is independently halogen, hydroxyl, cyano,
nitro, --N(R.sup.3).sub.2, --S(O).sub.tR.sup.4, --OR.sup.3,
optionally substituted C.sub.1-C.sub.6 alkyl, optionally
substituted C.sub.6-C.sub.10aryl, optionally substituted
C.sub.3-C.sub.8cycloalkyl, or optionally substituted
heteroaryl.
9. The compound of paragraph 1, wherein the compound is a compound
of formula (Ib):
##STR00072##
or a pharmaceutically acceptable salt thereof. 10. The compound of
paragraph 8 or 9, wherein R.sup.2 is hydrogen, hydroxyl, or
optionally substituted C.sub.1-C.sub.6 alkyl. 11. A pharmaceutical
composition comprising a compound of formula (I):
##STR00073##
or a pharmaceutically acceptable salt thereof, wherein: each of
X.sup.1, X.sup.2, X.sup.3, X.sup.4, X.sup.5, X.sup.6, X.sup.7,
X.sup.8, X.sup.9, and X.sup.10 is independently CR.sup.1 or N; Y is
O, C(R.sup.2).sub.2, or S(O).sub.t; each R.sup.1 is independently
hydrogen, halogen, hydroxyl, cyano, nitro, --N(R.sup.3).sub.2,
--S(O).sub.tR.sup.4, --OR.sup.3, optionally substituted
C.sub.1-C.sub.6 alkyl, optionally substituted C.sub.6-C.sub.10
aryl, optionally substituted C.sub.3-C.sub.8 cycloalkyl, optionally
substituted heteroaryl, or optionally substituted heterocyclyl;
each R.sup.2 is independently hydrogen, hydroxyl, or optionally
substituted C.sub.1-C.sub.6alkyl; or both R.sup.2 combine to form
.dbd.O, .dbd.S, or .dbd.NR.sup.5; R.sup.3 is hydrogen,
--SO.sub.2R.sup.4, optionally substituted C.sub.1-C.sub.6 alkyl,
optionally substituted C.sub.6-C.sub.10 aryl, optionally
substituted C.sub.3-C.sub.8 cycloalkyl, optionally substituted
heteroaryl, or optionally substituted heterocyclyl; each R.sup.4 is
independently optionally substituted C.sub.1-C.sub.6 alkyl,
optionally substituted C.sub.6-C.sub.10 aryl, optionally
substituted heteroaryl, or optionally substituted heterocyclyl;
R.sup.5 is hydrogen, hydroxyl, --S(O).sub.2R.sup.4, or optionally
substituted C.sub.1-C.sub.6 alkyl; and each t is independently 0,
1, or 2. 12. The pharmaceutical composition of paragraph 11,
wherein Y is C(R.sup.2).sub.2. 13. The pharmaceutical composition
of paragraph 11 or 12, wherein at least one R.sup.2 is hydrogen.
14. The pharmaceutical composition of paragraph 11 or 12, wherein
both R.sup.2 combine to form .dbd.O. 15. The pharmaceutical
composition of paragraph 11 or 12, wherein each R.sup.2 is
independently optionally substituted C.sub.1-C.sub.6 alkyl. 16. The
pharmaceutical composition of any one of paragraphs 11 to 15,
wherein each of X.sup.2 and X.sup.9 is independently CR.sup.1. 17.
The pharmaceutical composition of any one of paragraphs 11 to 16,
wherein at least two R.sup.1 groups are --N(R.sup.3).sub.2. 18. The
pharmaceutical composition of paragraph 11, wherein the compound is
a compound of formula (Ia):
##STR00074##
or a pharmaceutically acceptable salt thereof, wherein:
[0304] each R.sup.1 is independently halogen, hydroxyl, cyano,
nitro, --N(R.sup.3).sub.2, --S(O).sub.tR.sup.4, --OR.sup.3,
optionally substituted C.sub.1-C.sub.6 alkyl, optionally
substituted C.sub.6-C.sub.10aryl, optionally substituted
C.sub.3-C.sub.8cycloalkyl, or optionally substituted
heteroaryl.
19. The pharmaceutical composition of paragraph 11, wherein the
compound is a compound of formula (Ib):
##STR00075##
or a pharmaceutically acceptable salt thereof. 20. The
pharmaceutical composition of paragraph 18 or 19, wherein R.sup.2
is hydrogen, hydroxyl, or optionally substituted C.sub.1-C.sub.6
alkyl. 21. A pharmaceutical composition comprising a compound
selected from the group consisting of:
##STR00076##
and pharmaceutically acceptable salts thereof. 22. A compound of
formula (II):
##STR00077##
or a pharmaceutically acceptable salt thereof, wherein:
[0305] (i) R.sup.1A and R.sup.1B combine to form .dbd.O, .dbd.S,
.dbd.C(R.sup.6).sub.2, or .dbd.NR.sup.7; R.sup.2A and R.sup.2B
combine to form .dbd.O, .dbd.S, .dbd.C(R.sup.6).sub.2, or
.dbd.NR.sup.7; and R.sup.3A and R.sup.3B, together with the atoms
to which they are attached, combine to form a double bond; or
[0306] (ii) each of R.sup.1A and R.sup.2A is independently
hydrogen, halogen, hydroxyl, cyano, nitro, --S(O).sub.tR.sup.6, or
--OR.sup.7; R.sup.1B and R.sup.3A, together with the atoms to which
they are attached, combine to form a double bond; and R.sup.2B and
R.sup.3B, together with the atoms to which they are attached,
combine to form a double bond;
[0307] both R.sup.4, together with the atoms to which they are
attached, combine to form an optionally substituted heterocyclic
ring;
[0308] both R.sup.5, together with the atoms to which they are
attached, combine to form an optionally substituted heterocyclic
ring;
[0309] each R.sup.6 is independently hydrogen, halogen, cyano, or
optionally substituted C.sub.1-C.sub.6 alkyl;
[0310] each R.sup.7 is independently hydroxyl, optionally
substituted C.sub.1-C.sub.6 alkyl, optionally substituted
C.sub.6-C.sub.10 aryl, optionally substituted C.sub.3-C.sub.8
cycloalkyl, optionally substituted heteroaryl, or optionally
substituted heterocyclyl;
[0311] each t is independently 0, 1, or 2; and
[0312] the compound of formula (II) is not a compound selected from
the group consisting of:
##STR00078##
pharmaceutically acceptable salts thereof. 23. The compound of
paragraph 22, wherein both R.sup.4, together with the atoms to
which they are attached, combine to form an optionally substituted
heterocyclic ring comprising an endocyclic nitrogen atom. 24. The
compound of paragraph 22 or 23, wherein both R.sup.4, together with
the atoms to which they are attached, combine to form an optionally
substituted, 5-membered heterocyclic ring. 25. The compound of any
one of paragraphs 22 to 24, wherein both R.sup.5, together with the
atoms to which they are attached, combine to form an optionally
substituted heterocyclic ring comprising an endocyclic nitrogen
atom. 26. The compound of any one of paragraphs 22 to 25, wherein
both R.sup.5, together with the atoms to which they are attached,
combine to form an optionally substituted, 5-membered heterocyclic
ring. 27. The compound of paragraph 22, wherein the compound is a
compound of formula (IIa):
##STR00079##
or a pharmaceutically acceptable salt thereof, and each R.sup.8 is
independently H or optionally substituted C.sub.1-C.sub.6 alkyl.
28. The compound of any one of paragraphs 22 to 27, wherein
R.sup.1A and R.sup.1B combine to form .dbd.O. 29. The compound of
any one of paragraphs 22 to 28, wherein R.sup.2A and R.sup.2B
combine to form .dbd.O. 30. The compound of any one of paragraphs
22 to 27, wherein each of R.sup.1A and R.sup.2A is independently
hydrogen, halogen, or hydroxyl. 31. A pharmaceutical composition
comprising a compound of formula (II):
##STR00080##
or a pharmaceutically acceptable salt thereof, wherein:
[0313] (i) R.sup.1A and R.sup.1B combine to form .dbd.O, .dbd.S,
.dbd.C(R.sup.6).sub.2, or .dbd.NR.sup.7; R.sup.2A and R.sup.2B
combine to form .dbd.O, .dbd.S, .dbd.C(R.sup.6).sub.2, or
.dbd.NR.sup.7; and R.sup.3A and R.sup.3B, together with the atoms
to which they are attached, combine to form a double bond; or
[0314] (ii) each of R.sup.1A and R.sup.2A is independently
hydrogen, halogen, hydroxyl, cyano, nitro, --S(O)R.sup.6, or
--OR.sup.7; R.sup.1B and R.sup.3A, together with the atoms to which
they are attached, combine to form a double bond; and R.sup.2B and
R.sup.3B, together with the atoms to which they are attached,
combine to form a double bond;
[0315] both R.sup.4, together with the atoms to which they are
attached, combine to form an optionally substituted heterocyclic
ring;
[0316] both R.sup.5, together with the atoms to which they are
attached, combine to form an optionally substituted heterocyclic
ring;
[0317] each R.sup.6 is independently hydrogen, halogen, cyano, or
optionally substituted C.sub.1-C.sub.6 alkyl;
[0318] each R.sup.7 is independently hydroxyl, optionally
substituted C.sub.1-C.sub.6 alkyl, optionally substituted
C.sub.6-C.sub.10 aryl, optionally substituted C.sub.3-C.sub.8
cycloalkyl, optionally substituted heteroaryl, or optionally
substituted heterocyclyl; and
[0319] each t is independently 0, 1, or 2.
32. The pharmaceutical composition of paragraph 31, wherein both
R.sup.4, together with the atoms to which they are attached,
combine to form an optionally substituted heterocyclic ring
comprising an endocyclic nitrogen atom. 33. The pharmaceutical
composition of paragraph 31 or 32, wherein both R.sup.4, together
with the atoms to which they are attached, combine to form an
optionally substituted, 5-membered heterocyclic ring. 34. The
pharmaceutical composition of any one of paragraphs 31 to 33,
wherein both R.sup.5, together with the atoms to which they are
attached, combine to form an optionally substituted heterocyclic
ring comprising an endocyclic nitrogen atom.
[0320] 35. The pharmaceutical composition of any one of paragraphs
31 to 34, wherein both R.sup.5, together with the atoms to which
they are attached, combine to form an optionally substituted,
5-membered heterocyclic ring.
36. The pharmaceutical composition of paragraph 31, wherein the
compound is a compound of formula (IIa):
##STR00081##
or a pharmaceutically acceptable salt thereof, and each R.sup.8 is
independently H or optionally substituted C.sub.1-C.sub.6 alkyl.
37. The pharmaceutical composition of any one of paragraphs 31 to
36, wherein R.sup.1A and R.sup.1B combine to form .dbd.O. 38. The
pharmaceutical composition of any one of paragraphs 31 to 37,
wherein R.sup.2A and R.sup.2B combine to form .dbd.O. 39. The
pharmaceutical composition of any one of paragraphs 31 to 36,
wherein each of R.sup.1A and R.sup.2A is independently hydrogen,
halogen, or hydroxyl. 40. A pharmaceutical composition comprising a
compound selected from the group consisting of:
##STR00082##
and pharmaceutically acceptable salts thereof. 41. A compound of
formula (III):
##STR00083##
or a pharmaceutically acceptable salt thereof, wherein:
[0321] R.sup.1 is an optionally substituted C.sub.6-C.sub.10 aryl
or optionally substituted heteroaryl;
[0322] each R.sup.2 is independently hydrogen or an optionally
substituted C.sub.1-C.sub.6 alkyl; and
[0323] the compound of formula (III) is not a compound selected
from the group consisting of:
##STR00084##
and pharmaceutically acceptable salts thereof. 42. The compound of
paragraph 41, wherein R.sup.1 is optionally substituted
C.sub.6-C.sub.10 aryl. 43. The compound of paragraph 41 or 42,
wherein each R.sup.2 is hydrogen. 44. The compound of paragraph 41,
wherein the compound is a compound of formula (IIIa):
##STR00085##
or a pharmaceutically acceptable salt thereof, wherein: R.sup.3 is
optionally substituted C.sub.1-C.sub.6 alkyl, halogen, --OR.sup.4,
--S(O)R.sup.5, or --N(R.sup.4).sub.2; each R.sup.4 is independently
hydrogen or optionally substituted C.sub.1-C.sub.6 alkyl;
[0324] R.sup.5 is optionally substituted C.sub.1-C.sub.6 alkyl,
optionally substituted C.sub.6-C.sub.10 aryl, or optionally
substituted heteroaryl.
45. The compound of paragraph 44, wherein R.sup.3 is optionally
substituted C.sub.1-C.sub.6 alkyl or halogen. 46. A pharmaceutical
composition comprising a compound of formula (III):
##STR00086##
or a pharmaceutically acceptable salt thereof, wherein:
[0325] R.sup.1 is an optionally substituted C.sub.6-C.sub.10 aryl
or optionally substituted heteroaryl; and
[0326] each R.sup.2 is independently hydrogen or an optionally
substituted C.sub.1-C.sub.6 alkyl.
47. The pharmaceutical composition of paragraph 46, wherein R.sup.1
is optionally substituted C.sub.6-C.sub.10 aryl. 48. The
pharmaceutical composition of paragraph 46 or 47, wherein each
R.sup.2 is hydrogen. 49. The pharmaceutical composition of
paragraph 46, wherein the compound is a compound of formula
(IIIa):
##STR00087##
or a pharmaceutically acceptable salt thereof, wherein:
[0327] R.sup.3 is hydrogen, optionally substituted C.sub.1-C.sub.6
alkyl, halogen, cyano, --OR.sup.4, --S(O)R.sup.5, or
--N(R.sup.4).sub.2;
[0328] each R.sup.4 is independently hydrogen or optionally
substituted C.sub.1-C.sub.6 alkyl;
[0329] R.sup.5 is optionally substituted C.sub.1-C.sub.6 alkyl,
optionally substituted C.sub.6-C.sub.10 aryl, or optionally
substituted heteroaryl; and
[0330] each t is independently 0, 1, or 2.
50. The pharmaceutical composition of paragraph 49, wherein R.sup.3
is optionally substituted C.sub.1-C.sub.6 alkyl, hydrogen, halogen,
or cyano. 51. A pharmaceutical composition comprising a compound
selected from the group consisting of:
##STR00088##
and pharmaceutically acceptable salts thereof.
[0331] 52. A method of inhibiting interaction between IL18 and
IL18R in a medium comprising IL18 and a cell expressing IL18R, the
method comprising contacting the cell in the medium with a compound
of any one of paragraphs 1 to 51, wherein after the contacting step
the interaction between IL18 and IL18R is inhibited.
53. The method of paragraph 52, wherein the cell is in a subject.
54. The method of paragraph 52 or 53, wherein the medium is a
tissue or bodily fluid of a subject. 55. A method of treating an
inflammatory or autoimmune disorder in a subject in need thereof,
the method comprising administering a therapeutically effective
amount of the compound of any one of paragraphs 1 to 10, 22-30, and
41-45, or a pharmaceutically acceptable salt thereof, or the
pharmaceutical composition of any one of paragraphs 11 to 21, 31 to
40, and 46-51, to the subject. 56. The method of paragraph 55,
wherein the inflammatory or autoimmune disorder is selected from
the group consisting of rheumatoid arthritis, osteoarthritis,
lupus, psoriasis, inflammatory bowel disease, vascular graft
failure, heart disease, vascular disease, type 1 diabetes, type 2
diabetes, metabolic syndrome, diabetic wound healing, trauma, burn
wounds, Steven Johnsons syndrome, and kidney disease. 57. The
method of paragraph 56, wherein the inflammatory or autoimmune
disorder is a vascular graft failure. 58. The method of paragraph
57, wherein the vascular graft failure is a peripheral vascular
graft failure. 59. The method of paragraph 58, wherein the
peripheral vascular graft failure is a vein graft failure or
prosthetic graft failure. 60. The method of paragraph 57, wherein
the vascular graft failure is a coronary artery graft failure. 61.
The method of paragraph 60, wherein the coronary graft failure is
an is artery graft failure, vein graft failure, prosthetic graft
failure. 62. The method of paragraph 57, wherein the vascular graft
failure is restenosis after stent graft. 63. The method of
paragraph 57, wherein the vascular graft failure is restenosis
after balloon angioplasty. 64. The method of paragraph 56, wherein
the inflammatory or autoimmune disorder is a heart disease. 65. The
method of paragraph 64, wherein the heart disease is
cardiomyopathy, congestive heart failure, or ischemic coronary
heart disease. 66. The method of paragraph 55, wherein the
inflammatory or autoimmune disorder is a vascular disease. 67. The
method of paragraph 66, wherein the vascular disease is intimal
hyperplasia, atherosclerosis, coronary artery disease, restenosis,
primary hypertension, secondary hypertension, peripheral vascular
disease, or critical limb-threatening ischemia. 68. The method of
paragraph 56, wherein the inflammatory or autoimmune disorder is
type 1 diabetes, type 2 diabetes, metabolic syndrome, or diabetic
wound healing. 69. The method of paragraph 56, wherein the
inflammatory or autoimmune disorder is a kidney disease. 70. The
method of paragraph 69, wherein the kidney disease is a chronic
kidney disease, end-stage renal disease, or kidney failure. 71. The
method of paragraph 55, wherein the inflammatory or autoimmune
disorder is a cytokine storm. 72. The method of paragraph 55,
wherein the inflammatory or autoimmune disorder is endothelialitis.
73. The method of paragraph 55, 71, or 72, wherein the subject is
suffering from acute respiratory distress syndrome (ARDS). 74. The
method of paragraph 55, 71, 72, or 73, wherein the inflammatory or
autoimmune disorder is associated with an infection. 75. The method
of paragraph 74, wherein the infection is a beta-coronavirus
infection. 76. The method of paragraph 75, wherein the infection is
SARS-CoV-2, SARS-CoV, or MERS-CoV. 77. The method of paragraph 76,
wherein the infection is SARS-CoV-2. 78. The method of paragraph
55, wherein the inflammatory or autoimmune disorder is sepsis. 79.
The method of paragraph 55, 71, or 78, wherein the inflammatory or
autoimmune disorder is associated with a viremia, bacteremia,
protozoan infection, or fungal infection. 80. A method of treating
a cancer in a subject in need thereof, the method comprising
administering a therapeutically effective amount of the compound of
any one of paragraphs 1 to 10, 22-30, and 41-45, or a
pharmaceutically acceptable salt thereof, or the pharmaceutical
composition of any one of paragraphs 11 to 21, 31 to 40, and 46-51,
to the subject. 81. The method of paragraph 80, wherein the cancer
is gastric cancer, colon cancer, melanoma, and multiple
myeloma.
[0332] Other embodiments are within the scope of the claims.
* * * * *